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Lee WS, Choi SJ, Shin YH, Kim JK. Mesenchymal Stem Cells Expressing Baculovirus-Engineered Brain-Derived Neurotrophic Factor Improve Peripheral Nerve Regeneration in a Rat Model. Tissue Eng Regen Med 2025; 22:351-362. [PMID: 39962026 PMCID: PMC11926320 DOI: 10.1007/s13770-025-00703-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 12/20/2024] [Accepted: 01/13/2025] [Indexed: 03/21/2025] Open
Abstract
BACKGROUND Peripheral nerve injuries are a major clinical challenge because of their complex nature and limited regenerative capacity. This study aimed to improve peripheral nerve regeneration using Wharton's jelly mesenchymal stem cells (WJ-MSCs) engineered to express brain-derived neurotrophic factor (BDNF) via a baculovirus (BV) vector. The cells were evaluated for efficacy when seeded into acellular nerve grafts (ANGs) in a rat sciatic nerve defect model. METHODS WJ-MSCs were transfected with recombinant BV to upregulate BDNF expression. Conditioned medium (CM) from these cells was utilized to treat Schwann cells (SCs), and the impact on myelination-related markers, including KROX20, myelin basic protein (MBP), glial fibrillary acidic protein (GFAP), and S100 calcium-binding protein β (S100β), and the activation of the mammalian target of rapamycin (mTOR)/ protein kinase B (AKT)/p38 signaling pathways were evaluated. In vivo, BDNF-expressing WJ-MSCs were seeded into ANGs and implanted into a rat sciatic nerve defect model. Functional recovery was evaluated via video gait analysis, isometric tetanic force measurement, muscle weight evaluation, ankle contracture angle measurement, and histological analysis using toluidine blue staining. RESULTS BDNF expression was significantly upregulated in WJ-MSCs post-transfection. BDNF-MSC CM substantially promoted the expression of myelination markers in SCs and activated the mTOR/AKT/p38 signaling pathway. In the rat model, seeding of ANGs with BDNF-expressing WJ-MSCs resulted in improved functional outcomes, including enhanced toe-off angles, increased isometric tetanic force, greater muscle weight recovery, and a higher total number of myelinated axons compared with controls. CONCLUSION WJ-MSCs engineered to express BDNF significantly enhanced peripheral nerve regeneration when utilized in conjunction with ANGs. These findings indicate BDNF-expressing WJ-MSCs are a promising therapeutic approach for treating peripheral nerve injuries.
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Affiliation(s)
- Won Sun Lee
- Department of Orthopedic Surgery Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic Road 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Soon Jin Choi
- Asan Institute for Life Sciences, Seoul, Republic of Korea
| | - Young Ho Shin
- Department of Orthopedic Surgery Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic Road 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Jae Kwang Kim
- Department of Orthopedic Surgery Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic Road 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea.
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Gurel M, Zomer H, McFetridge C, Murfee WL, McFetridge PS. Physiologically-Modeled Dynamic Stimulation and Growth Factors Induce Differentiation of Mesenchymal Stem Cells to a Vascular Endothelial Cell Phenotype. Microcirculation 2025; 32:e70007. [PMID: 40120632 PMCID: PMC12012511 DOI: 10.1111/micc.70007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 03/04/2025] [Accepted: 03/14/2025] [Indexed: 03/25/2025]
Abstract
OBJECTIVE Mesenchymal stem cells (MSCs) represent an attractive option as an endothelial cell (EC) source for regenerative medicine therapies. However, the differentiation of MSCs toward an ECs phenotype can be regulated by a complex and dynamic microenvironment, including specific growth factors as well as local mechanical cues. The objective of this work was to evaluate whether Physiologically-modeled dynamic stimulation (PMDS) characterized by continuous variability in pulse frequencies mimicking the dynamic temporal range of cardiac function would enhance MSC differentiation toward ECs compared to a constant frequency stimulation. METHODS Mesenchymal stem cells were grown in a complex growth factor cocktail versus standard culture media to initiate the endothelial differentiation process, then subsequently exposed to PMDS that vary in duration and constant flow (CF) at a fixed 10 dynes/cm2 shear stress and 1.3 Hz frequency. RESULTS Both PMDS and media type strongly influence cell differentiation and function. Cells were shown to significantly upregulate eNOS activity and displayed lower TNF-a induced leukocyte adhesion compared to cells cultured under CF, consistent with a more quiescent ECs phenotype that regulates anti-inflammatory and anti-thrombotic states. CONCLUSION These findings suggest that the dynamic microenvironment created by perfusion, in contrast to constant frequency, combined with growth factors, enhances MSCs differentiation toward a vascular endothelial-like phenotype.
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Affiliation(s)
- Mediha Gurel
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
- Biotechnology Research and Application Center, Cukurova University, Adana, Turkey
- Electronic and Automation Department, Bitlis Eren University, Bitlis, Turkey
| | - Helena Zomer
- Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA
| | - Calum McFetridge
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
| | - Walter L Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
| | - Peter S McFetridge
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
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Yea JH, Jo CH. Dose- and sex-dependent effects on umbilical cord-derived mesenchymal stem cell efficacy in regeneration of a full-thickness tendon defect in a rat model. Clin Shoulder Elb 2025; 28:49-59. [PMID: 40077873 PMCID: PMC11938924 DOI: 10.5397/cise.2024.00626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 11/21/2024] [Accepted: 12/02/2024] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have shown potential in regenerative medicine. In the present study the effects of MSC dosage and recipient sex on tendon regeneration were evaluated. METHODS A full-thickness tendon defect (FTTD) was created on supraspinatus tendons (SSTs) of rats and cryoprotective solution (CPS) and MSCs (0.05, 0.1 and 0.5 million MSCs [M-MSC] for female groups and 1.0 M-MSC for both female and male groups) were applied. After 2 and 4 weeks, macroscopic and histological evaluations were performed. RESULTS Total macroscopic scores were improved in all MSC groups compared with the CPS group, with no significant differences among the MSC groups. Furthermore, all MSC groups had lower total degenerative scores than the CPS group; however, only 0.1 M-MSC, 0.5 M-MSC, and 1 M-MSC groups showed significantly improved hyalinization compared with the CPS group at 4 weeks. Collagen organization and coherence were higher in all MSC groups than in the CPS group at both 2 and 4 weeks; however, 0.5 M-MSC and 1 M-MSC groups scored better than the 0.05 M-MSC group at 4 weeks. Heterotopic matrix analysis revealed smaller glycosaminoglycan (GAG)-rich areas in the 0.1 M-MSC, 0.5 M-MSC, and 1 M-MSC groups compared with the CPS group at 4 weeks. Overall, macroscopic and histological evaluations were not significantly different between female and male groups except for GAG-rich area. CONCLUSIONS The MSC dosage affected collagen and heterotopic matrix formation in a FTTD rat model; however, the efficacy of MSCs (1.0 M dose) in collagen regeneration was not affected based on the sex of the recipient. Level of evidence: I.
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Affiliation(s)
- Ji-Hye Yea
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
- Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, USA
- Department of Translational Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Chris Hyunchul Jo
- Department of Translational Medicine, Seoul National University College of Medicine, Seoul, Korea
- Department of Orthopedic Surgery, SMG-SNU Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
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Atta H, Kassem DH, Kamal MM, Hamdy NM. Harnessing the ubiquitin proteasome system as a key player in stem cell biology. Biofactors 2025; 51:e2157. [PMID: 39843166 DOI: 10.1002/biof.2157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Accepted: 12/20/2024] [Indexed: 01/24/2025]
Abstract
Intracellular proteins take part in almost every body function; thus, protein homeostasis is of utmost importance. The ubiquitin proteasome system (UPS) has a fundamental role in protein homeostasis. Its main role is to selectively eradicate impaired or misfolded proteins, thus halting any damage that could arise from the accumulation of these malfunctioning proteins. Proteasomes have a critical role in controlling protein homeostasis in all cell types, including stem cells. We will discuss the role of UPS enzymes as well as the 26S proteasome complex in stem cell biology from several angles. First, we shall overview common trends of proteasomal activity and gene expression of different proteasomal subunits and UPS enzymes upon passaging and differentiation of stem cells toward various cell lineages. Second, we shall explore the effect of modulating proteasomal activity in stem cells and navigate through the interrelation between proteasomes' activity and various proteasome-related transcription factors. Third, we will shed light on curated microRNAs and long non-coding RNAs using various bioinformatics tools that might have a possible role in regulating UPS in stem cells and possibly, upon manipulation, can enhance the differentiation process into different lineages and/or delay senescence upon cell passaging. This will help to decipher the role played by individual UPS enzymes and subunits as well as various interrelated molecular mediators in stem cells' maintenance and/or differentiation and open new avenues in stem cell research. This can ultimately provide a leap toward developing novel therapeutic interventions related to proteasome dysregulation.
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Affiliation(s)
- Hind Atta
- School of Life and Medical Sciences, University of Hertfordshire Hosted By Global Academic Foundation, Cairo, Egypt
| | - Dina H Kassem
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Mohamed M Kamal
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
- Pharmacology and Biochemistry Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt
- Drug Research and Development Group, Health Research Center of Excellence, The British University in Egypt, Cairo, Egypt
| | - Nadia M Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
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Zhang S, Tseng SCG. Presence of heavy chain-hyaluronan/pentraxin 3 (HC-HA/PTX3) complex in human umbilical cord. Tissue Cell 2024; 91:102535. [PMID: 39217785 DOI: 10.1016/j.tice.2024.102535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 07/26/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024]
Abstract
The heavy chain (HC)-hyaluronan (HA)/pentraxin 3 (HC-HA/PTX3) complex is formed by tumor necrosis factor-stimulated gene-6 (TSG-6) catalyzing the covalent (ester bond) transfer of HC1 from inter-α-trypsin inhibitor (IαI) to HA followed by tight binding of PTX3. The presence of such a complex has been found in human amniotic membrane (AM) and is considered to be a major matrix component responsible for its anti‑inflammatory and anti‑scarring properties to promote regenerative healing. Because the therapeutic potentials of AM and umbilical cord (UC) are similar, we herein evaluated whether human UC also contains HC-HA/PTX3. Immunostaining of UC cross-sections showed abundant PTX3, HC1, HA, TSG-6, and bikunin. Western blot analysis suggested the presence of HC1 complex bound via a NaOH-sensitive bond and tightly bound to PTX3 multimer in UC and AM extracts but not in chorion and placenta extracts. HC-HA/PTX3 was purified from UC extract by successive runs of density gradient ultracentrifugation and verified the presence of HC1 but not HC2 or HC3 based on western blot analysis. These results suggest the presence of HC-HA/PTX3 complex in UC is similar to AM.
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Affiliation(s)
- Suzhen Zhang
- BioTissue Holdings Inc., 7300 Corporate Center Dr Suite 700, Miami, FL, USA
| | - Scheffer C G Tseng
- BioTissue Holdings Inc., 7300 Corporate Center Dr Suite 700, Miami, FL, USA.
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Athiel Y, Cariot L, Jouannic JM, Maillet C, Mauffré V, Adam C, Huet H, Larghero J, Nasone J, Guilbaud L. Safety and efficacy of human umbilical cord-derived mesenchymal stromal cells in fetal ovine myelomeningocele repair. Stem Cell Res Ther 2024; 15:444. [PMID: 39568021 PMCID: PMC11580231 DOI: 10.1186/s13287-024-03991-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 10/09/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND The aim of this study was to assess the safety and efficacy of human umbilical cord mesenchymal stromal cells (hUC-MSCs) patch used as an adjuvant therapy in fetal myelomeningocele (MMC) surgery in the ovine model. METHODS hUC-MSCs were isolated from human umbilical cords (UC) using the explant method, cultured and characterized. hUC-MSCs were then embedded in a fibrin patch. MMC were surgically created at 75 days of gestation and repaired at 89 days of gestation in sheep fetuses. Two groups were compared: the hUC-MSCs group in which MMC was repaired using a cellular patch and the control group, in which MMC was repaired using an acellular patch. Safety was evaluated by clinical ewes' monitoring during gestation, and clinical and histological examinations of lambs after birth. Efficacy was assessed by clinical neurological evaluation at 2 and 24 h of life using the sheep locomotor rating scale and by histological analyses. RESULTS Among the 17 operated lambs, nine were born alive: six in the hUC-MSCs group and three in the control group. Overall fetal loss was 47% (8/17) without differences between the two groups. No fever was reported in ewes. No tumors were detected in clinical and histological examinations in the lambs. At 24 h of life, mean Sheep Locomotor Rating score was higher in the hUC-MSCs group than in the control group: 15.0 versus 2.0 (p = 0.07). Histological analyses showed a higher large neurons density in the hUC-MSCs group in comparison with the control group: 9.9 versus 6.3/mm2 of gray matter (p = 0.04). Lambs in the hUC-MSCs group had lower fibrosis around the spinal cord and at the level of the MMC scar: 70.9 versus 253.7 μm (p = 0.10) and 691.3 versus 1684.4 μm (p = 0,18), respectively. CONCLUSIONS Ovine fetal repair of MMC using human UC-MSCs seems to be an effective and safe procedure.
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Affiliation(s)
- Yoann Athiel
- Service de médecine foetale, DMU ORIGYN, APHP, Hôpital Trousseau, Sorbonne Université, Paris, France
- Unité de Thérapie Cellulaire, Université Paris Cité, AP-HP, Hôpital Saint-Louis, U976 et CIC de Biothérapies, INSERM, Paris, France
| | - Laura Cariot
- Service de médecine foetale, DMU ORIGYN, APHP, Hôpital Trousseau, Sorbonne Université, Paris, France
- Unité de Thérapie Cellulaire, Université Paris Cité, AP-HP, Hôpital Saint-Louis, U976 et CIC de Biothérapies, INSERM, Paris, France
| | - Jean-Marie Jouannic
- Service de médecine foetale, DMU ORIGYN, APHP, Hôpital Trousseau, Sorbonne Université, Paris, France
- Working Group Spina Bifida and Other Dysraphisms, European Reference Network ITHACA, Paris, France
| | - Corentin Maillet
- Service de médecine foetale, DMU ORIGYN, APHP, Hôpital Trousseau, Sorbonne Université, Paris, France
- Unité de Thérapie Cellulaire, Université Paris Cité, AP-HP, Hôpital Saint-Louis, U976 et CIC de Biothérapies, INSERM, Paris, France
| | - Vincent Mauffré
- École Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
| | - Clovis Adam
- Service d'anatomopathologie, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Hélène Huet
- École Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
| | - Jérôme Larghero
- Unité de Thérapie Cellulaire, Université Paris Cité, AP-HP, Hôpital Saint-Louis, U976 et CIC de Biothérapies, INSERM, Paris, France
| | - Justine Nasone
- Unité de Thérapie Cellulaire, Université Paris Cité, AP-HP, Hôpital Saint-Louis, U976 et CIC de Biothérapies, INSERM, Paris, France
| | - Lucie Guilbaud
- Service de médecine foetale, DMU ORIGYN, APHP, Hôpital Trousseau, Sorbonne Université, Paris, France.
- Unité de Thérapie Cellulaire, Université Paris Cité, AP-HP, Hôpital Saint-Louis, U976 et CIC de Biothérapies, INSERM, Paris, France.
- Working Group Spina Bifida and Other Dysraphisms, European Reference Network ITHACA, Paris, France.
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Silva Couto P, Stibbs DJ, Rotondi MC, Khalife R, Wolf D, Takeuchi Y, Rafiq QA. Biological differences between adult and perinatal human mesenchymal stromal cells and their impact on the manufacturing processes. Cytotherapy 2024; 26:1429-1441. [PMID: 38970611 DOI: 10.1016/j.jcyt.2024.05.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 05/10/2024] [Accepted: 05/22/2024] [Indexed: 07/08/2024]
Abstract
The biological properties of human mesenchymal stromal cells (hMSCs) have been explored in over a thousand clinical trials in the last decade. Although hMSCs can be isolated from multiple sources, the degree of biological similarity between cell populations from these sources remains to be determined. A comparative study was performed investigating the growth kinetics and functionality of hMSCs isolated from adipose tissue (AT), bone marrow (BM) and umbilical cord tissue (UCT) expanded in monolayer over five passages. Adult hMSCs (AT, BM) had a slower proliferation ability than the UCT-hMSCs, with no apparent differences in their glucose consumption profile. BM-hMSCs produced higher concentrations of endogenous vascular endothelial growth factor (VEGF) compared to AT- and UCT-hMSCs. This study also revealed that UCT-hMSCs were more efficiently transduced by a lentiviral vector carrying a VEGF gene than their adult counterparts. Following cellular immunophenotypic characterization, no differences across the sources were found in the expression levels of the typical markers used to identify hMSCs. This work established a systematic approach for cell source selection depending on the hMSC's intended clinical application.
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Affiliation(s)
- Pedro Silva Couto
- Department of Biochemical Engineering, University College London, London, UK
| | - Dale J Stibbs
- Department of Biochemical Engineering, University College London, London, UK
| | - Marco C Rotondi
- Department of Biochemical Engineering, University College London, London, UK
| | - Rana Khalife
- Department of Biochemical Engineering, University College London, London, UK
| | | | - Yasuhiro Takeuchi
- Division of Infection and Immunity, University College London, London, UK; Biotherapeutics and Advanced Therapies, Scientific Research and Innovation, Medicines and Healthcare products Regulatory Agency, Potters Bar, UK
| | - Qasim A Rafiq
- Department of Biochemical Engineering, University College London, London, UK.
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Lai S, Guo Z. Stem cell therapies for chronic obstructive pulmonary disease: mesenchymal stem cells as a promising treatment option. Stem Cell Res Ther 2024; 15:312. [PMID: 39300523 DOI: 10.1186/s13287-024-03940-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 09/16/2024] [Indexed: 09/22/2024] Open
Abstract
Chronic obstructive pulmonary disease(COPD) is an inflammatory disease characterized by the progressive and irreversible structural and functional damage of lung tissue. Although COPD is a significant global disease burden, the available treatments only ameliorate the symptoms, but cannot reverse lung damage. Researchers in regenerative medicine have examined the use of stem cell transplantation for treatment of COPD and other diseases because these cells have the potential for unlimited self-renewal and the ability to undergo directed differentiation. Stem cells are typically classified as embryonic stem cells, induced pluripotent stem cells, and adult stem cells (which includes mesenchymal stem cells [MSCs]), each with its own advantages and disadvantages regarding applications in regenerative medicine. Although the heterogeneity and susceptibility to senescence of MSCs make them require careful consideration for clinical applications. However, the low tumourigenicity and minimal ethical concerns of MSCs make them appear to be excellent candidates. This review summarizes the characteristics of various stem cell types and describes their therapeutic potential in the treatment of COPD, with a particular emphasis on MSCs. We aim to facilitate subsequent in-depth research and preclinical applications of MSCs by providing a comprehensive overview.
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Affiliation(s)
- Sumei Lai
- Stem Cell Laboratory, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
| | - Zhifeng Guo
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
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Carreira M, Pires-Santos M, Correia CR, Nadine S, Mano JF. Liquefied capsules containing nanogrooved microdiscs and umbilical cord-derived cells for bone tissue engineering. OPEN RESEARCH EUROPE 2024; 4:94. [PMID: 39279819 PMCID: PMC11393531 DOI: 10.12688/openreseurope.17000.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Accepted: 09/05/2024] [Indexed: 09/18/2024]
Abstract
Background Surface topography has been shown to influence cell behavior and direct stromal cell differentiation into distinct lineages. Whereas this phenomenon has been verified in two-dimensional cultures, there is an urgent need for a thorough investigation of topography's role within a three-dimensional (3D) environment, as it better replicates the natural cellular environment. Methods A co-culture of Wharton's jelly-derived mesenchymal stem/stromal cells (WJ-MSCs) and human umbilical vein endothelial cells (HUVECs) was encapsulated in a 3D system consisting of a permselective liquefied environment containing freely dispersed spherical microparticles (spheres) or nanogrooved microdiscs (microdiscs). Microdiscs presenting 358 ± 23 nm grooves and 944 ± 49 nm ridges were produced via nanoimprinting of spherical polycaprolactone microparticles between water-soluble polyvinyl alcohol counter molds of nanogrooved templates. Spheres and microdiscs were cultured in vitro with umbilical cord-derived cells in a basal or osteogenic medium within liquefied capsules for 21 days. Results WJ-MSCs and HUVECs were successfully encapsulated within liquefied capsules containing spheres and microdiscs, ensuring high cellular viability. Results show an enhanced osteogenic differentiation in microdiscs compared to spheres, even in basal medium, evidenced by alkaline phosphatase activity and osteopontin expression. Conclusions This work suggests that the topographical features present in microdiscs induce the osteogenic differentiation of adhered WJ-MSCs along the contact guidance, without additional differentiation factors. The developed 3D bioencapsulation system comprising topographical features might be suitable for bone tissue engineering approaches with minimum in vitro manipulation.
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Affiliation(s)
- Mariana Carreira
- CICECO – Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Aveiro, Aveiro District, 3810-193, Portugal
| | - Manuel Pires-Santos
- CICECO – Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Aveiro, Aveiro District, 3810-193, Portugal
| | - Clara R Correia
- CICECO – Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Aveiro, Aveiro District, 3810-193, Portugal
| | - Sara Nadine
- CICECO – Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Aveiro, Aveiro District, 3810-193, Portugal
| | - João F Mano
- CICECO – Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Aveiro, Aveiro District, 3810-193, Portugal
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Safwan M, Bourgleh MS, Aldoush M, Haider KH. Tissue-source effect on mesenchymal stem cells as living biodrugs for heart failure: Systematic review and meta-analysis. World J Cardiol 2024; 16:469-483. [PMID: 39221190 PMCID: PMC11362808 DOI: 10.4330/wjc.v16.i8.469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 06/24/2024] [Accepted: 07/23/2024] [Indexed: 08/26/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs), as living biodrugs, have entered advanced phases of clinical assessment for cardiac function restoration in patients with myocardial infarction and heart failure. While MSCs are available from diverse tissue sources, bone-marrow-derived MSCs (BM-MSCs) remain the most well-studied cell type, besides umbilical-cord-derived MSCs (UC-MSCs). The latter offers advantages, including noninvasive availability without ethical considerations. AIM To compare the safety and efficacy of BM-MSCs and UC-MSCs in terms of left ventricular ejection fraction (LVEF), 6-min walking distance (6MWD), and major adverse cardiac events (MACEs). METHODS Five databases were systematically searched to identify randomized controlled trials (RCTs). Thirteen RCTs (693 patients) were included using predefined eligibility criteria. Weighted mean differences and odds ratio (OR) for the changes in the estimated treatment effects. RESULTS UC-MSCs significantly improved LVEF vs controls by 5.08% [95% confidence interval (CI): 2.20%-7.95%] at 6 mo and 2.78% (95%CI: 0.86%-4.70%) at 12 mo. However, no significant effect was observed for BM-MSCs vs controls. No significant changes were observed in the 6MWD with either of the two cell types. Also, no differences were observed for MACEs, except rehospitalization rates, which were lower only with BM-MSCs (odds ratio 0.48, 95%CI: 0.24-0.97) vs controls. CONCLUSION UC-MSCs significantly improved LVEF compared with BM-MSCs. Their advantageous characteristics position them as a promising alternative to MSC-based therapy.
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Affiliation(s)
- Moaz Safwan
- Department of Basic Sciences, Sulaiman Al Rajhi University, Al Bukairiyah 51941, Saudi Arabia
| | - Mariam Safwan Bourgleh
- Department of Basic Sciences, Sulaiman Al Rajhi University, Al Bukairiyah 51941, Saudi Arabia
| | - Mohamed Aldoush
- Department of Basic Sciences, Sulaiman Al Rajhi University, Al Bukairiyah 51941, Saudi Arabia
| | - Khawaja Husnain Haider
- Department of Basic Sciences, Sulaiman Al Rajhi University, Al Bukairiyah 51941, Saudi Arabia.
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Lee SB, Abdal Dayem A, Kmiecik S, Lim KM, Seo DS, Kim HT, Kumar Biswas P, Do M, Kim DH, Cho SG. Efficient improvement of the proliferation, differentiation, and anti-arthritic capacity of mesenchymal stem cells by simply culturing on the immobilized FGF2 derived peptide, 44-ERGVVSIKGV-53. J Adv Res 2024; 62:119-141. [PMID: 37777063 PMCID: PMC11331723 DOI: 10.1016/j.jare.2023.09.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 08/23/2023] [Accepted: 09/26/2023] [Indexed: 10/02/2023] Open
Abstract
INTRODUCTION The stem cell microenvironment has been evidenced to robustly affect its biological functions and clinical grade. Natural or synthetic growth factors, especially, are essential for modulating stem cell proliferation, metabolism, and differentiation via the interaction with specific extracellular receptors. Fibroblast growth factor-2 (FGF-2) possesses pleiotropic functions in various tissues and organs. It interacts with the FGF receptor (FGFR) and activates FGFR signaling pathways, which involve numerous biological functions, such as angiogenesis, wound healing, cell proliferation, and differentiation. OBJECTIVES Here, we aim to explore the molecular functions, mode of action, and therapeutic activity of yet undetermined function, FGF-2-derived peptide, FP2 (44-ERGVVSIKGV-53) in promoting the proliferation, differentiation, and therapeutic application of human Wharton's jelly mesenchymal stem cells (hWJ-MSCs) in comparison to other test peptides, canofin1 (FP1), hexafin2 (FP3), and canofin3 (FP4) with known functions. METHODS The immobilization of test peptides that are fused with mussel adhesive proteins (MAP) on the culture plate was carried out via EDC/NHS chemistry. Cell Proliferation assay, colony-forming unit, western blotting analysis, gene expression analysis, RNA-Seq. analysis, osteogenic, and chondrogenic differentiation capacity were applied to test the activity of the test peptides. We additionally utilized three-dimensional (3D) structural analysis and artificial intelligence (AI)-based AlphaFold2 and CABS-dock programs for receptor interaction prediction of the peptide receptor. We also verified the in vivo therapeutic capacity of FP2-cultured hWJ-MSCs using an osteoarthritis mice model. RESULTS Culture of hWJ-MSC onto an FP2-immobilized culture plate showed a significant increase in cell proliferation (n = 3; *p < 0.05, **p < 0.01) and the colony-forming unit (n = 3; *p < 0.05, **p < 0.01) compared with the test peptides. FP2 showed a significantly upregulated phosphorylation of FRS2α and FGFR1 and activated the AKT and ERK signaling pathways (n = 3; *p < 0.05, **p < 0.01, ***p < 0.001). Interestingly, we detected efficient FP2 receptor binding that was predicted using AI-based tools. Treatment with an AKT inhibitor significantly abrogated the FP2-mediated enhancement of cell differentiation (n = 3; *p < 0.05, **p < 0.01, ***p < 0.001). Intra-articular injection of FP2-cultured MSCs significantly mitigated arthritis symptoms in an osteoarthritis mouse model, as shown through the functional tests (n = 10; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001), modulation of the expression level of the pro-inflammatory and anti-inflammatory genes, and improved osteochondral regeneration as demonstrated by tissue sections. CONCLUSION Our study identified the FGF-2-derived peptide FP2 as a promising candidate peptide to improve the therapeutic potential of hWJ-MSCs, especially in bone and cartilage regeneration.
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Affiliation(s)
- Soo Bin Lee
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Ahmed Abdal Dayem
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Sebastian Kmiecik
- Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, 02-089 Warsaw, Poland
| | - Kyung Min Lim
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea; R&D Team, StemExOne Co., Ltd., 307 KU Technology Innovation Bldg, 120, Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Dong Sik Seo
- Stem Cell Research Center of AMOLIFESCIENCE Co., Ltd, 91, Gimpo-daero 1950 Beon-gil, Tongjin-eup, Gimpo-si, Gyeonggi-do 10014, Republic of Korea
| | - Hyeong-Taek Kim
- Stem Cell Research Center of AMOLIFESCIENCE Co., Ltd, 91, Gimpo-daero 1950 Beon-gil, Tongjin-eup, Gimpo-si, Gyeonggi-do 10014, Republic of Korea
| | - Polash Kumar Biswas
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Minjae Do
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205 USA
| | - Deok-Ho Kim
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205 USA
| | - Ssang-Goo Cho
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea; R&D Team, StemExOne Co., Ltd., 307 KU Technology Innovation Bldg, 120, Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
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Sharma P, Maurya DK. Wharton's jelly mesenchymal stem cells: Future regenerative medicine for clinical applications in mitigation of radiation injury. World J Stem Cells 2024; 16:742-759. [PMID: 39086560 PMCID: PMC11287430 DOI: 10.4252/wjsc.v16.i7.742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 05/28/2024] [Accepted: 06/24/2024] [Indexed: 07/25/2024] Open
Abstract
Wharton's jelly mesenchymal stem cells (WJ-MSCs) are gaining significant attention in regenerative medicine for their potential to treat degenerative diseases and mitigate radiation injuries. WJ-MSCs are more naïve and have a better safety profile, making them suitable for both autologous and allogeneic transplantations. This review highlights the regenerative potential of WJ-MSCs and their clinical applications in mitigating various types of radiation injuries. In this review, we will also describe why WJ-MSCs will become one of the most probable stem cells for future regenerative medicine along with a balanced view on their strengths and weaknesses. Finally, the most updated literature related to both preclinical and clinical usage of WJ-MSCs for their potential application in the regeneration of tissues and organs will also be compiled.
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Affiliation(s)
- Prashasti Sharma
- Life Sciences, Homi Bhabha National Institute, Mumbai 400094, Maharashtra, India
- Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400085, Maharashtra, India
| | - Dharmendra Kumar Maurya
- Life Sciences, Homi Bhabha National Institute, Mumbai 400094, Maharashtra, India
- Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400085, Maharashtra, India.
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13
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Fu Y, Zhang C, Yang Y, Zhou B, Yang M, Zhu G, Zhu Y. Effect of umbilical cord blood-mononuclear cells on knee osteoarthritis in rabbits. J Orthop Surg Res 2024; 19:323. [PMID: 38811966 PMCID: PMC11138004 DOI: 10.1186/s13018-024-04815-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Accepted: 05/27/2024] [Indexed: 05/31/2024] Open
Abstract
BACKGROUND To investigate the effect and underlying mechanism of umbilical cord blood-mononuclear cells (UCB-MNCs) in treating knee osteoarthritis (KOA) in rabbits. METHODS A rabbit KOA model was prepared by anterior cruciate ligament transection (ACLT). Fifty New Zealand white rabbits were randomly divided into the control group, model group, sodium hyaluronate (SH) group, platelet-rich plasma (PRP) group and UCB-MNC group. Knee injections were performed once a week for five consecutive weeks. The gross view of the knee joint, morphology of knee cartilage and structural changes in the knee joint were observed on CT scans, and graded by the Lequesne MG behavioral score and the Mankin score. TNF-α and IL-1β levels in the synovial fluid of the knee were measured by the enzyme-linked immunosorbent assay (ELISA). Expression levels of MMP-13 and COL-II in the knee cartilage were detected by Western blotting and qRT-PCR. RESULTS The Lequesne MG behavioral score and the Mankin score were significantly higher in the model group than those in the control group (P < 0.05). Rabbits in the SH, PRP and UCB-MNC groups had sequentially lower scores than those in the model group. Imaging features of KOA were more pronounced in the model group than in the remaining groups. CB-MNC significantly relieved KOA, compared to SH and PRP. Significantly higher levels of TNF-α and IL-1β in the synovial fluid of the knee, and up-regulated MMP-13 and down-regulated COL-II in the knee cartilage were detected in the model group than in the control group. These changes were significantly reversed by the treatment with SH, PRP and UCB-MNCs, especially UCB-MNCs. CONCLUSION Injections of UCB-MNCs into knees protect the articular cartilage and hinder the progression of KOA in rabbits by improving the local microenvironment at knee joints.
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Affiliation(s)
- Yuhang Fu
- The Second School of Clinical Medicine of Binzhou Medical University, Yantai, 264199, Shandong Province, China
- Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264199, Shandong Province, China
| | - Chi Zhang
- Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264199, Shandong Province, China
| | - Yong Yang
- Yantai City Yantai Mountain Hospital, Yantai, 264008, Shandong Province, China
| | - Baisui Zhou
- Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264199, Shandong Province, China
| | - Meng Yang
- The Second School of Clinical Medicine of Binzhou Medical University, Yantai, 264199, Shandong Province, China
- Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264199, Shandong Province, China
| | - Guoshuai Zhu
- Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264199, Shandong Province, China
| | - Yonglin Zhu
- Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264199, Shandong Province, China.
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Nadeem G, Theerakittayakorn K, Somredngan S, Thi Nguyen H, Boonthai T, Samruan W, Tangkanjanavelukul P, Parnpai R. Induction of Human Wharton's Jelly of Umbilical Cord Derived Mesenchymal Stem Cells to Be Chondrocytes and Transplantation in Guinea Pig Model with Spontaneous Osteoarthritis. Int J Mol Sci 2024; 25:5673. [PMID: 38891860 PMCID: PMC11171648 DOI: 10.3390/ijms25115673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 05/16/2024] [Accepted: 05/17/2024] [Indexed: 06/21/2024] Open
Abstract
Osteoarthritis (OA) is a degenerative joint disease commonly found in elderly people and obese patients. Currently, OA treatments are determined based on their condition severity and a medical professional's advice. The aim of this study was to differentiate human Wharton's jelly-derived mesenchymal stem cells (hWJ-MSCs) into chondrocytes for transplantation in OA-suffering guinea pigs. hWJ-MSCs were isolated using the explant culture method, and then, their proliferation, phenotypes, and differentiation ability were evaluated. Subsequently, hWJ-MSCs-derived chondrocytes were induced and characterized based on immunofluorescent staining, qPCR, and immunoblotting techniques. Then, early-OA-suffering guinea pigs were injected with hyaluronic acid (HA) containing either MSCs or 14-day-old hWJ-MSCs-derived chondrocytes. Results showed that hWJ-MSCs-derived chondrocytes expressed specific markers of chondrocytes including Aggrecan, type II collagen, and type X collagen proteins and β-catenin, Sox9, Runx2, Col2a1, Col10a1, and ACAN gene expression markers. Administration of HA plus hWJ-MSCs-derived chondrocytes (HA-CHON) produced a better recovery rate of degenerative cartilages than HA plus MSCs or only HA. Histological assessments demonstrated no significant difference in Mankin's scores of recovered cartilages between HA-CHON-treated guinea pigs and normal articular cartilage guinea pigs. Transplantation of hWJ-MSCs-derived chondrocytes was more effective than undifferentiated hWJ-MSCs or hyaluronic acid for OA treatment in guinea pigs. This study provides a promising treatment to be used in early OA patients to promote recovery and prevent disease progression to severe osteoarthritis.
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Affiliation(s)
- Gulrez Nadeem
- Embryo Technology and Stem Cell Research Center, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand; (G.N.); (K.T.); (S.S.); (H.T.N.); (T.B.); (W.S.)
| | - Kasem Theerakittayakorn
- Embryo Technology and Stem Cell Research Center, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand; (G.N.); (K.T.); (S.S.); (H.T.N.); (T.B.); (W.S.)
| | - Sirilak Somredngan
- Embryo Technology and Stem Cell Research Center, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand; (G.N.); (K.T.); (S.S.); (H.T.N.); (T.B.); (W.S.)
| | - Hong Thi Nguyen
- Embryo Technology and Stem Cell Research Center, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand; (G.N.); (K.T.); (S.S.); (H.T.N.); (T.B.); (W.S.)
| | - Traimat Boonthai
- Embryo Technology and Stem Cell Research Center, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand; (G.N.); (K.T.); (S.S.); (H.T.N.); (T.B.); (W.S.)
| | - Worawalan Samruan
- Embryo Technology and Stem Cell Research Center, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand; (G.N.); (K.T.); (S.S.); (H.T.N.); (T.B.); (W.S.)
| | - Ponthep Tangkanjanavelukul
- School of Orthopedic Surgery, Institute of Medicine, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand
| | - Rangsun Parnpai
- Embryo Technology and Stem Cell Research Center, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand; (G.N.); (K.T.); (S.S.); (H.T.N.); (T.B.); (W.S.)
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Arellano MYG, VanHeest M, Emmadi S, Abdul-Hafez A, Ibrahim SA, Thiruvenkataramani RP, Teleb RS, Omar H, Kesaraju T, Mohamed T, Madhukar BV, Omar SA. Role of Mesenchymal Stem/Stromal Cells (MSCs) and MSC-Derived Extracellular Vesicles (EVs) in Prevention of Telomere Length Shortening, Cellular Senescence, and Accelerated Biological Aging. Bioengineering (Basel) 2024; 11:524. [PMID: 38927760 PMCID: PMC11200821 DOI: 10.3390/bioengineering11060524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 05/11/2024] [Accepted: 05/13/2024] [Indexed: 06/28/2024] Open
Abstract
Biological aging is defined as a progressive decline in tissue function that eventually results in cell death. Accelerated biologic aging results when the telomere length is shortened prematurely secondary to damage from biological or environmental stressors, leading to a defective reparative mechanism. Stem cells therapy may have a potential role in influencing (counteract/ameliorate) biological aging and maintaining the function of the organism. Mesenchymal stem cells, also called mesenchymal stromal cells (MSCs) are multipotent stem cells of mesodermal origin that can differentiate into other types of cells, such as adipocytes, chondrocytes, and osteocytes. MSCs influence resident cells through the secretion of paracrine bioactive components such as cytokines and extracellular vesicles (EVs). This review examines the changes in telomere length, cellular senescence, and normal biological age, as well as the factors contributing to telomere shortening and accelerated biological aging. The role of MSCs-especially those derived from gestational tissues-in prevention of telomere shortening (TS) and accelerated biological aging is explored. In addition, the strategies to prevent MSC senescence and improve the antiaging therapeutic application of MSCs and MSC-derived EVs in influencing telomere length and cellular senescence are reviewed.
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Affiliation(s)
- Myrna Y. Gonzalez Arellano
- Division of Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (M.Y.G.A.); (A.A.-H.); (S.A.I.); (R.P.T.); (R.S.T.); (H.O.); (T.K.); (T.M.); (B.V.M.)
- College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (M.V.); (S.E.)
- Regional Neonatal Intensive Care Unit, Sparrow Hospital, Lansing, MI 48912, USA
| | - Matthew VanHeest
- College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (M.V.); (S.E.)
| | - Sravya Emmadi
- College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (M.V.); (S.E.)
| | - Amal Abdul-Hafez
- Division of Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (M.Y.G.A.); (A.A.-H.); (S.A.I.); (R.P.T.); (R.S.T.); (H.O.); (T.K.); (T.M.); (B.V.M.)
- College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (M.V.); (S.E.)
| | - Sherif Abdelfattah Ibrahim
- Division of Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (M.Y.G.A.); (A.A.-H.); (S.A.I.); (R.P.T.); (R.S.T.); (H.O.); (T.K.); (T.M.); (B.V.M.)
- College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (M.V.); (S.E.)
- Histology and Cell Biology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Ranga P. Thiruvenkataramani
- Division of Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (M.Y.G.A.); (A.A.-H.); (S.A.I.); (R.P.T.); (R.S.T.); (H.O.); (T.K.); (T.M.); (B.V.M.)
- College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (M.V.); (S.E.)
- Regional Neonatal Intensive Care Unit, Sparrow Hospital, Lansing, MI 48912, USA
| | - Rasha S. Teleb
- Division of Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (M.Y.G.A.); (A.A.-H.); (S.A.I.); (R.P.T.); (R.S.T.); (H.O.); (T.K.); (T.M.); (B.V.M.)
- College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (M.V.); (S.E.)
- Department of Pediatrics and Neonatology, Qena Faculty of Medicine, South Valley University, Qena 83523, Egypt
| | - Hady Omar
- Division of Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (M.Y.G.A.); (A.A.-H.); (S.A.I.); (R.P.T.); (R.S.T.); (H.O.); (T.K.); (T.M.); (B.V.M.)
| | - Tulasi Kesaraju
- Division of Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (M.Y.G.A.); (A.A.-H.); (S.A.I.); (R.P.T.); (R.S.T.); (H.O.); (T.K.); (T.M.); (B.V.M.)
| | - Tarek Mohamed
- Division of Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (M.Y.G.A.); (A.A.-H.); (S.A.I.); (R.P.T.); (R.S.T.); (H.O.); (T.K.); (T.M.); (B.V.M.)
- College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (M.V.); (S.E.)
- Regional Neonatal Intensive Care Unit, Sparrow Hospital, Lansing, MI 48912, USA
| | - Burra V. Madhukar
- Division of Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (M.Y.G.A.); (A.A.-H.); (S.A.I.); (R.P.T.); (R.S.T.); (H.O.); (T.K.); (T.M.); (B.V.M.)
- College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (M.V.); (S.E.)
| | - Said A. Omar
- Division of Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (M.Y.G.A.); (A.A.-H.); (S.A.I.); (R.P.T.); (R.S.T.); (H.O.); (T.K.); (T.M.); (B.V.M.)
- College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (M.V.); (S.E.)
- Regional Neonatal Intensive Care Unit, Sparrow Hospital, Lansing, MI 48912, USA
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Athiel Y, Jouannic JM, Mauffré V, Dehan C, Adam C, Blot S, Lallemant P, De Saint Denis T, Larghero J, Nasone J, Guilbaud L. Allogenic umbilical cord-derived mesenchymal stromal cells improve motor function in prenatal surgical repair of myelomeningocele: An ovine model study. BJOG 2024; 131:759-767. [PMID: 37492999 DOI: 10.1111/1471-0528.17624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 07/05/2023] [Accepted: 07/11/2023] [Indexed: 07/27/2023]
Abstract
OBJECTIVE To investigate the effects of an adjuvant allogenic umbilical cord mesenchymal stromal cell (UC-MSC) patch applied during fetal surgery on motor and sphincter function in the ovine MMC model. DESIGN MMC defects were surgically created at 75 days of gestation and repaired 14 days later. POPULATION Ovine MMC model: fetal lambs. METHODS We compared lambs that received a UC-MSC patch with a control group of lambs that received an acellular patch. MAIN OUTCOME MEASURES Clinical neurological assessment was performed at 2 and 24 hours of life and included determination of the Sheep Locomotor Rating scale (SLR), which has been validated in the ovine MMC model. Electrophysical examinations, spine scans and histological analyses were also performed. RESULTS Of the 13 operated lambs, nine were born alive: five had of these had received a UC-MSC patch and four an acellular patch. At 24 hours of life, lambs in the UC-MSC group had a significantly higher score (14 versus 5, P = 0.04). Amyotrophy was significantly more common in the control group (75% versus 0%, P = 0.02). All the lambs in the control group and none of those in the UC-MSC group were incontinent. No significant differences were observed between the UC-MSC and control groups in terms of the presence of spontaneous EMG activity, nerve conduction or spinal evoked potentials. In the microscopic examination, lambs in the UC-MSC group had less fibrosis between the spinal cord and the dermis (mean thickness, 453 versus 3921 μm, P = 0.03) and around the spinal cord (mean thickness, 47 versus 158 μm, P < 0.001). Examination of the spinal cord in the area of the MMC defect showed a higher large neuron density in the UC-MSC group (14.5 versus 5.6 neurons/mm2, P < 0.001). No tumours were observed. CONCLUSIONS Fetal repair of MMC using UC-MSC patches improves motor and sphincter function as well as spinal preservation and reduction of fibrosis.
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Affiliation(s)
- Yoann Athiel
- Université Paris Cité, INSERM, U976 et Centre d'Investigation Clinique en Biothérapies CIC-BT CBT501, INSERM, Paris, France
- Service de médecine fœtale, APHP, Hôpital Trousseau, DMU ORIGYNE, Sorbonne Université, Paris, France
| | - Jean-Marie Jouannic
- Université Paris Cité, INSERM, U976 et Centre d'Investigation Clinique en Biothérapies CIC-BT CBT501, INSERM, Paris, France
- Service de médecine fœtale, APHP, Hôpital Trousseau, DMU ORIGYNE, Sorbonne Université, Paris, France
- Working Group Spina Bifida and Other Dysraphisms, European Reference Network ITHACA, Paris, France
| | - Vincent Mauffré
- Université Paris-Saclay, UVSQ, INRAE, BREED, Jouy-en-Josas, France
- École Nationale Vétérinaire d'Alfort, BREED, Maison-Alfort, France
| | - Coralie Dehan
- Université Paris-Saclay, UVSQ, INRAE, BREED, Jouy-en-Josas, France
- École Nationale Vétérinaire d'Alfort, BREED, Maison-Alfort, France
| | - Clovis Adam
- Service d'anatomopathologie, Hôpital Bicêtre, Le Kremlin Bicêtre, France
| | - Stéphane Blot
- U955-IMRB, Inserm, École Nationale Vétérinaire d'Alfort, Unité de Neurologie, Maisons-Alfort, France
| | - Pauline Lallemant
- National Reference Center for Rare Disease: Vertebral and Spinal Cord Anomalies (MAVEM Center), AP-HP, Trousseau Hospital, Paris, France
- Sorbonne University, AP-HP, Trousseau Hospital, Paris, France
| | - Timothé De Saint Denis
- Service de Neurochirurgie Pédiatrique, Centre de Référence Chiari, Syringomyélie et Malformations du Rachis et de la Moelle C-MAVEM, et Centre de Référence des Malformations Craniofaciales-CRMR, Paris, France
| | - Jérôme Larghero
- Université Paris Cité, INSERM, U976 et Centre d'Investigation Clinique en Biothérapies CIC-BT CBT501, INSERM, Paris, France
- Unité de Thérapie Cellulaire et Centre MEARY de Thérapie Cellulaire et Génique, AP-HP, Hôpital Saint-Louis, Paris, France
| | - Justine Nasone
- Université Paris Cité, INSERM, U976 et Centre d'Investigation Clinique en Biothérapies CIC-BT CBT501, INSERM, Paris, France
- Unité de Thérapie Cellulaire et Centre MEARY de Thérapie Cellulaire et Génique, AP-HP, Hôpital Saint-Louis, Paris, France
| | - Lucie Guilbaud
- Université Paris Cité, INSERM, U976 et Centre d'Investigation Clinique en Biothérapies CIC-BT CBT501, INSERM, Paris, France
- Service de médecine fœtale, APHP, Hôpital Trousseau, DMU ORIGYNE, Sorbonne Université, Paris, France
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Baptistella JC, da Silva CG, Báo SN, Panegossi LC, Cardoso TC, de Carvalho RG, Martins CF. Immunomodulatory-associated gene transcripts to multipotency of bovine amniotic fluid mesenchymal stem cells. Anim Reprod 2024; 21:e20230155. [PMID: 38628495 PMCID: PMC11019794 DOI: 10.1590/1984-3143-ar2023-0155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 03/04/2024] [Indexed: 04/19/2024] Open
Abstract
The adnexa fetal tissues are sources of mesenchymal stromal cells (MSCs) due to their noninvasive harvest, with all biological material discarded most of the time. MSCs are a promise regarding to their plasticity, self-renewal, differentiation potentials, immunomodulatory and anti-inflammatory properties, which have made clinical stem cell therapy a reality. The present study aimed to characterize and evaluate the immunomodulation ability of bovine mesenchymal cells collected from bovine amniotic fluid (bAFMSCs) isolated and subjected to sixth consecutive culture passages in vitro. The multilineage properties of the bAFMSCs collections confirmed the ability to undergo adipogenic, chondrogenic and osteogenic differentiation. The mesenchymal gene transcription CD106, CD73, CD29, CD90 and CD166 were detected in bAFMSCs, whereas CD34 and CD45 were not detected. Regarding cytokine mRNA expression, IL2, IL6, INFα, INFβ, INFγ, TNFα and TNFβ were downregulated, while IL10 was highly regulated in all studied passages. The present study demonstrated the immunological properties and multipotency of in vitro bAFMSCs collections, and thus, they can be tested in cattle pathological treatments or multiplication by nuclear transfer cloning.
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Affiliation(s)
- Jamila Cristina Baptistella
- Laboratório de Virologia e Cultura Celular, Faculdade de Medicina Veterinária, Universidade Estadual Paulista – UNESP, Araçatuba, SP, Brasil
- Faculdade de Medicina Veterinária, Centro Universitário Católico Salesiano – UniSalesiano, Araçatuba, SP, Brasil
| | - Carolina Gonzales da Silva
- Instituto Federal de Educação, Ciência e Tecnologia da Bahia, Campus Xique-Xique, Xique-Xique, BA, Brasil
| | - Sônia Nair Báo
- Departamento de Biologia Celular, Instituto de Ciências Biológicas, Universidade de Brasília – UnB, Brasília, DF, Brasil
| | - Letícia Colin Panegossi
- Laboratório de Virologia e Cultura Celular, Faculdade de Medicina Veterinária, Universidade Estadual Paulista – UNESP, Araçatuba, SP, Brasil
| | - Tereza Cristina Cardoso
- Laboratório de Virologia e Cultura Celular, Faculdade de Medicina Veterinária, Universidade Estadual Paulista – UNESP, Araçatuba, SP, Brasil
| | - Roberto Gameiro de Carvalho
- Laboratório de Virologia e Cultura Celular, Faculdade de Medicina Veterinária, Universidade Estadual Paulista – UNESP, Araçatuba, SP, Brasil
| | - Carlos Frederico Martins
- Laboratório de Reprodução Animal, Empresa Brasileira de Pesquisa Agropecuária – Embrapa Cerrados, Planaltina, DF, Brasil
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Ryu HS, Abueva C, Padalhin A, Park SY, Yoo SH, Seo HH, Chung PS, Woo SH. Oral ulcer treatment using human tonsil-derived mesenchymal stem cells encapsulated in trimethyl chitosan hydrogel: an animal model study. Stem Cell Res Ther 2024; 15:103. [PMID: 38589946 PMCID: PMC11003084 DOI: 10.1186/s13287-024-03694-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 03/08/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND Oral ulcers are a common side effect of chemotherapy and affect patients' quality of life. While stem cell transplantation is a potential treatment for oral ulcers, its efficacy is limited as the stem cells tend to remain in the affected area for a short time. This study aims to develop a treatment for oral ulcers by using trimethyl chitosan (TMC) hydrogel with human tonsil-derived stem cells (hTMSCs) to increase the therapeutic effect of stem cells and investigate their effectiveness. METHODS Animals were divided into four experimental groups: Control, TMC hydrogel, hTMSCs, and hTMSCs loaded in TMC hydrogel (Hydrogel + hTMSCs) (each n = 8). Oral ulcers were chemically induced by anesthetizing the rats followed by injection of dilute acetic acid in the right buccal mucosa. After confirming the presence of oral ulcers in the animals, a single subcutaneous injection of 100 µL of each treatment was applied to the ulcer area. Histological analyses were performed to measure inflammatory cells, oral mucosal thickness, and fibrosis levels. The expression level of inflammatory cytokines was also measured using RT-PCR to gauge therapeutic the effect. RESULTS The ulcer size was significantly reduced in the TMC hydrogel + hTMSCs group compared to the control group. The stem cells in the tissue were only observed until Day 3 in the hTMSCs treated group, while the injected stem cells in the TMC Hydrogel + hTMSCs group were still present until day 7. Cytokine analysis related to the inflammatory response in the tissue confirmed that the TMC Hydrogel + hTMSCs treated group demonstrated superior wound healing compared to other experimental groups. CONCLUSION This study has shown that the adhesion and viability of current stem cell therapies can be resolved by utilizing a hydrogel prepared with TMC and combining it with hTMSCs. The combined treatment can promote rapid healing of oral cavity wounds by enhancing anti-inflammatory effects and expediting wound healing. Therefore, hTMSC loaded in TMC hydrogel was the most effective wound-healing approach among all four treatment groups prolonging stem cell survival. However, further research is necessary to minimize the initial inflammatory response of biomaterials and assess the safety and long-term effects for potential clinical applications.
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Affiliation(s)
- Hyun Seok Ryu
- Beckman Laser Institute Korea, Dankook University College of Medicine, Cheonan, Republic of Korea
- Medical Laser Research Center, Dankook University College of Medicine, Cheonan, Republic of Korea
| | - Celine Abueva
- Beckman Laser Institute Korea, Dankook University College of Medicine, Cheonan, Republic of Korea
- Medical Laser Research Center, Dankook University College of Medicine, Cheonan, Republic of Korea
| | - Andrew Padalhin
- Beckman Laser Institute Korea, Dankook University College of Medicine, Cheonan, Republic of Korea
- Medical Laser Research Center, Dankook University College of Medicine, Cheonan, Republic of Korea
| | - So Young Park
- Beckman Laser Institute Korea, Dankook University College of Medicine, Cheonan, Republic of Korea
| | - Seung Hyeon Yoo
- School of Medical Laser, Dankook University, Cheonan, Republic of Korea
| | - Hwee Hyon Seo
- School of Medical Laser, Dankook University, Cheonan, Republic of Korea
| | - Phil-Sang Chung
- Beckman Laser Institute Korea, Dankook University College of Medicine, Cheonan, Republic of Korea
- Medical Laser Research Center, Dankook University College of Medicine, Cheonan, Republic of Korea
- Department of Otorhinolaryngology-Head and Neck Surgery, Dankook University College of Medicine, 201 Manghyang-ro, Dongnam-gu, Cheonan, 31116, Republic of Korea
| | - Seung Hoon Woo
- Beckman Laser Institute Korea, Dankook University College of Medicine, Cheonan, Republic of Korea.
- Medical Laser Research Center, Dankook University College of Medicine, Cheonan, Republic of Korea.
- Department of Otorhinolaryngology-Head and Neck Surgery, Dankook University College of Medicine, 201 Manghyang-ro, Dongnam-gu, Cheonan, 31116, Republic of Korea.
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Fereydani NM, Galehdari H, Hoveizi E, Alghasi A, Ajami M. Ex vivo expansion of hematopoietic stem cells in two/ three-dimensional co-cultures with various source of stromal cells. Tissue Cell 2024; 87:102331. [PMID: 38430847 DOI: 10.1016/j.tice.2024.102331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 01/19/2024] [Accepted: 02/13/2024] [Indexed: 03/05/2024]
Abstract
The ex vivo expansion of hematopoietic stem cells, with both high quantities and quality, is considered a paramount issue in cell and gene therapy for hematological diseases. Complex interactions between the bone marrow microenvironment and hematopoietic stem cells reveal the importance of using 2D and 3D coculture as a physiological system simulator in the proliferation, differentiation, and homeostasis of HSCs. Herein, the capacity of mesenchymal stem cells derived from different sources to support the expansion and maintenance of HSPC was compared with each other. We evaluated the fold increase of HSPC, CD34 marker expression, cytokine secretion profile of different MSCs, and the frequency of hematopoietic colony-forming unit parameters. Our results show that there was no significant difference between adipose tissue-MSC, Wharton jelly-MSC, and Endometrial-MSCs in HSPC expansion (fold increase: 34.74±4.38 in Wj-MSC, 32.22±5.07 in AD-MSC, 25.9±1.27 in En-MSCs); However, there were significantly more than the expansion media alone (4.4±0.69). The results obtained from the cytokine secretion analysis also confirm these results. Also, there were significant differences in the clonogenicity of Wj-MSC, En-MSCs, and expansion media (CFU-GEMM: 7±1.73, 2.3±1.15, and 2.3±1.52), which indicated that Wj-MSC could significantly maintain the primitive state. As a result, using Wj-mesenchymal stem cells on a 3D coculture system effectively increases the HSPC expansion and maintains the colonization potential of hematopoietic stem cells.
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Affiliation(s)
- Nasim Mayeli Fereydani
- Department of Biology, Faculty of Sciences, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Hamid Galehdari
- Department of Biology, Faculty of Sciences, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
| | - Elham Hoveizi
- Department of Biology, Faculty of Sciences, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Arash Alghasi
- Thalassemia & Hemoglobinopathy Research center, Health research institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Monireh Ajami
- Department of Hematology, School of Paramedical Sciences, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
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Chen S, Duan X, He Y, Chen W. METTL3 promotes osteogenic differentiation of human umbilical cord mesenchymal stem cells by up-regulating m6A modification of circCTTN. Biosci Rep 2024; 44:BSR20231186. [PMID: 38358895 PMCID: PMC10932744 DOI: 10.1042/bsr20231186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 02/10/2024] [Accepted: 02/13/2024] [Indexed: 02/17/2024] Open
Abstract
BACKGROUND Human umbilical cord mesenchymal stem cells (hUCMSCs) are promising seed cells in bone tissue engineering. circRNA and N6-methyladenosine (m6A) RNA methylation play important roles in osteogenic differentiation. Here, we investigated the potential relevance of a critical circRNA, hsa_circ_0003376 (circCTTN), and methyltransferase-like 3 (METTL3) in osteogenic differentiation of hUCMSCs. METHODS Expression of circCTTN after hUCMSC osteogenic induction was detected by qRT-PCR. Three databases (RMBase v2.0, BERMP, and SRAMP) were used to predict m6A sites of circCTTN. RNA was enriched by methylated RNA immunoprecipitation (MeRIP), followed by quantitative real-time polymerase chain reaction to detect m6A level of circCTTN after METTL3 overexpression and osteogenic induction. RNA pull-down, Western blotting, and protein mass spectrometry were performed to investigate the potential mechanisms by which METTL3 promoted m6A modification of circCTTN. Bioinformatic analyses based on database (STRING) search and co-immunoprecipitation were used to analyze the proteins that interacted with METTL3. RESULTS Overexpression of METTL3 promoted osteogenic differentiation of hUCMSCs and increased m6A level of circCTTN. Two potential m6A modification sites of circCTTN were predicted. No direct interaction between METTL3 and circCTTN was observed. Thirty-one proteins were pulled down by probes specific for circCTTN, including NOP2, and two m6A reading proteins, EIF3A and SND1. Bioinformatics analysis and co-immunoprecipitation showed that METTL3 interacted with EIF3A indirectly through NOP2. CONCLUSIONS METTL3 promotes the osteogenic differentiation of hUCMSCs by increasing the m6A level of circCTTN. However, METTL3 does not bind directly to circCTTN. METTL3 interacts with circCTTN indirectly through NOP2 and EIF3A.
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Affiliation(s)
- Shujiang Chen
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China school of Stomatology, Sichuan University, Chengdu, Sichuan, China
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Xiaoqiong Duan
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, Sichuan, China
| | - Yanjin He
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China school of Stomatology, Sichuan University, Chengdu, Sichuan, China
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Wenchuan Chen
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China school of Stomatology, Sichuan University, Chengdu, Sichuan, China
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
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21
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Zhu H, Guo X, Zhang Y, Khan A, Pang Y, Song H, Zhao H, Liu Z, Qiao H, Xie J. The Combined Anti-Aging Effect of Hydrolyzed Collagen Oligopeptides and Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells on Human Skin Fibroblasts. Molecules 2024; 29:1468. [PMID: 38611748 PMCID: PMC11013016 DOI: 10.3390/molecules29071468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/08/2024] [Accepted: 03/18/2024] [Indexed: 04/14/2024] Open
Abstract
Stem cell-derived exosomes (SC-Exos) are used as a source of regenerative medicine, but certain limitations hinder their uses. The effect of hydrolyzed collagen oligopeptides (HCOPs), a functional ingredient of SC-Exos is not widely known to the general public. We herein evaluated the combined anti-aging effects of HCOPs and exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-Exos) using a senescence model established on human skin fibroblasts (HSFs). This study discovered that cells treated with HucMSC-Exos + HCOPs enhanced their proliferative and migratory capabilities; reduced both reactive oxygen species production and senescence-associated β-galactosidase activity; augmented type I and type III collagen expression; attenuated the expression of matrix-degrading metalloproteinases (MMP-1, MMP-3, and MMP-9), interleukin 1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α); and decreased the expression of p16, p21, and p53 as compared with the cells treated with HucMSC-Exos or HCOPs alone. These results suggest a possible strategy for enhancing the skin anti-aging ability of HucMSC-Exos with HCOPs.
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Affiliation(s)
- Huimin Zhu
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China; (H.Z.); (X.G.); (Y.Z.); (Y.P.); (H.S.); (H.Z.); (Z.L.)
| | - Xin Guo
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China; (H.Z.); (X.G.); (Y.Z.); (Y.P.); (H.S.); (H.Z.); (Z.L.)
| | - Yongqing Zhang
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China; (H.Z.); (X.G.); (Y.Z.); (Y.P.); (H.S.); (H.Z.); (Z.L.)
| | - Ajab Khan
- Department of Veterinary Pathology, Faculty of Veterinary and Animal Sciences, The University of Agriculture, Dera Ismail Khan 29050, Pakistan;
| | - Yinuo Pang
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China; (H.Z.); (X.G.); (Y.Z.); (Y.P.); (H.S.); (H.Z.); (Z.L.)
| | - Huifang Song
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China; (H.Z.); (X.G.); (Y.Z.); (Y.P.); (H.S.); (H.Z.); (Z.L.)
| | - Hong Zhao
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China; (H.Z.); (X.G.); (Y.Z.); (Y.P.); (H.S.); (H.Z.); (Z.L.)
| | - Zhizhen Liu
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China; (H.Z.); (X.G.); (Y.Z.); (Y.P.); (H.S.); (H.Z.); (Z.L.)
| | - Hua Qiao
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China; (H.Z.); (X.G.); (Y.Z.); (Y.P.); (H.S.); (H.Z.); (Z.L.)
| | - Jun Xie
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China; (H.Z.); (X.G.); (Y.Z.); (Y.P.); (H.S.); (H.Z.); (Z.L.)
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Shen J, Wu L, Shi X, Chen G, Liu T, Xu F, Xu X, Kou X, Zhao Y, Wang H, Wang C, Gao S, Xu S. Transplantation of the LRP1 high subpopulation of human umbilical cord-derived mesenchymal stem cells improves ovarian function in mice with premature ovarian failure and aged mice. Stem Cell Res Ther 2024; 15:64. [PMID: 38438896 PMCID: PMC10913679 DOI: 10.1186/s13287-024-03660-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 02/07/2024] [Indexed: 03/06/2024] Open
Abstract
BACKGROUND Premature ovarian failure (POF) has a profound impact on female reproductive and psychological health. In recent years, the transplantation of umbilical cord-derived mesenchymal stem cells (UC-MSCs) has demonstrated unprecedented potential in the treatment of POF. However, the heterogeneity of human UC-MSCs remains a challenge for their large-scale clinical application. Therefore, it is imperative to identify specific subpopulations within UC-MSCs that possess the capability to improve ovarian function, with the aim of reducing the uncertainty arising from the heterogeneity while achieving more effective treatment of POF. METHODS 10 × Genomics was performed to investigate the heterogeneity of human UC-MSCs. We used LRP1 as a marker and distinguished the potential therapeutic subpopulation by flow cytometry, and determined its secretory functions. Unsorted UC-MSCs, LRP1high and LRP1low subpopulation was transplanted under the ovarian capsules of aged mice and CTX-induced POF mice, and therapeutic effects was evaluated by assessing hormone levels, estrous cycles, follicle counts, and embryo numbers. RNA sequencing on mouse oocytes and granulosa cells after transplantation was performed to explore the mechanism of LRP1high subpopulation on mouse oocytes and granulosa cells. RESULTS We identified three distinct functional subtypes, including mesenchymal stem cells, multilymphoid progenitor cells and trophoblasts. Additionally, we identified the LRP1high subpopulation, which improved ovarian function in aged and POF mice. We elucidated the unique secretory functions of the LRP1high subpopulation, capable of secreting various chemokines, cytokines, and growth factors. Furthermore, LRP1 plays a crucial role in regulating the ovarian microenvironment, including tissue repair and extracellular matrix remodeling. Consistent with its functions, the transcriptomes of oocytes and granulosa cells after transplantation revealed that the LRP1high subpopulation improves ovarian function by modulating the extracellular matrix of oocytes, NAD metabolism, and mitochondrial function in granulosa cells. CONCLUSION Through exploration of the heterogeneity of UC-MSCs, we identified the LRP1high subpopulation capable of improving ovarian function in aged and POF mice by secreting various factors and remodeling the extracellular matrix. This study provides new insights into the targeted exploration of human UC-MSCs in the precise treatment of POF.
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Affiliation(s)
- Jiacheng Shen
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Li Wu
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
| | - Xiaoying Shi
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedics, Tongji Hospital, School of Life Science and Technology, Tongji University, Tongji, 200092, China
- Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Gang Chen
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Tingwei Liu
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Fangfang Xu
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Xiaocui Xu
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Xiaochen Kou
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
- Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Yanhong Zhao
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
- Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Hong Wang
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
- Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Chenfei Wang
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedics, Tongji Hospital, School of Life Science and Technology, Tongji University, Tongji, 200092, China
- Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Shaorong Gao
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
- Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
| | - Shaohua Xu
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
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Maurya DK, Sandur SK. Future Perspectives of Wharton's Jelly Mesenchymal Stem Cells and their Soluble Factors in Radioprotection. Curr Stem Cell Res Ther 2024; 19:781-784. [PMID: 36655527 DOI: 10.2174/1574888x18666230119103905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/29/2022] [Accepted: 12/06/2022] [Indexed: 01/20/2023]
Abstract
Acute radiation syndrome (ARS) is also known as triple syndrome, which develops after whole-body radiation exposure. During unforeseen exposures, these syndromes are set in depending on the dose of radiation. Cell-based therapy, especially using stem cells and their soluble factors, is gaining wide attention in the field of regenerative medicine to treat various diseases, including degenerative diseases. Stem cells attract prime attention because of their profound inherent tissue repair capability and regeneration potential. Further, stem cell therapy can be one of the promising strategies for the amelioration of ARS because of its ability to lodge in damaged tissue and release regenerative cytokines by sensing the local injury. In this regard, human Wharton's jelly-derived mesenchymal stem cells (hWJ-MSCs) have gained substantial attention for their applications in the treatment of various human diseases due to several advantages offered by them. This article is intended to provide future perspective on the use of WJ-MSCs for the management of accidental radiation injury in pre-clinical models, and finally, their utility in regeneration of damaged tissues and organs.
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Affiliation(s)
- Dharmendra Kumar Maurya
- Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai, 400 085, India
- Homi Bhabha National Institute, Anushaktinagar, Mumbai, 400 094, India
| | - Santosh Kumar Sandur
- Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai, 400 085, India
- Homi Bhabha National Institute, Anushaktinagar, Mumbai, 400 094, India
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Wang S, Yao Z, Chen L, Li J, Chen S, Fan C. Preclinical assessment of IL-1β primed human umbilical cord mesenchymal stem cells for tendon functional repair through TGF-β/IL-10 signaling. Heliyon 2023; 9:e21411. [PMID: 37954299 PMCID: PMC10638607 DOI: 10.1016/j.heliyon.2023.e21411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 10/19/2023] [Accepted: 10/20/2023] [Indexed: 11/14/2023] Open
Abstract
Background Inadequate repair capacity and disturbed immune compartments are the main pathological causes of tendinopathy. Transplantation of mesenchymal stem cells (MSCs) become an effective clinic option to alleviate tendinopathy. Interleukin-1β (IL-1β) could confer on MSCs enhanced immunoregulatory capability to remodel the repair microenvironment favoring tissue repair. Therefore, IL-1β activated UC-MSCs (1βUC-MSCs) may exert favorable efficacy in promoting tendon repair in a preclinical tendinopathy rat model. Methods Tendon-derived stem cells (TDSCs) were isolated and characterized. In vitro, the levels of immunoregulatory-related cytokines such as IL-1β, IL-6, IL-10, and TGF-β secreted by 1βUC-MSCs and unprimed UC-MSCs was measured. And tendon-specific markers expressed by TDSCs cultured with primed cultured medium (CM) or unprimed CM were detected. In vivo, Achilles tendinopathy was induced by 30 μL collagenase I injection in Sprague Dawley rats. One week later, the rats were randomly injected with UC-MSCs primed with IL-1β (106 cells per tendon), UC-MSCs, or PBS. After rats were sacrificed, histological evaluation, electron microscopy, biomechanical tests, gait performance were conducted to evaluate the structural and functional recovery of Achilles tendons. The inflammation and metabolic state of the extracellular matrix, and the potential mechanism were assessed by immunohistochemical staining and Western blot. Results UC-MSCs were activated by IL-1β to secrete higher levels of IL-10 and TGF-β while the secretion levels of IL-6 and IL-1β were not changed significantly, promoting a higher expression level of COL I and TNMD in TDSCs under proinflammatory environment. In vivo, the transplanted 1βUC-MSCs could survive up to 5 weeks after injection with tenogenic differentiation and improved tendon healing histologically semi-quantified by modified Bonar scores. This structural regeneration was further confirmed by observation of ultrastructural morphology, and led to good functional recovery including improved biomechanical properties and gait performance. During this process, the inflammatory response and metabolism of the extracellular matrix was improved through TGF-β/IL-10 pathway. Conclusion This study demonstrated that the transplantation of UC-MSCs activated by IL-1β exhibited satisfactory ability for promoting tendon functional repair in a tendinopathy rat model. During this process, the balance of inflammatory response and extracellular matrix metabolism was remodeled, and the TGF-β/Smad2/3 and IL-10 signaling pathways were activated simultaneously. We cautiously conclude that the IL-1β primed UC-MSCs could be a promising strategy for enhancing the ability of MSCs to treat tendinopathy.
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Affiliation(s)
- Shikun Wang
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai, China
| | - Zhixiao Yao
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai, China
| | - Lei Chen
- Department of Orthopedics, Tongji Hospital, School of Medicine Tongji University, Shanghai, China
| | - Juehong Li
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai, China
| | - Shuai Chen
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai, China
| | - Cunyi Fan
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai, China
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25
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Acuto S, Lo Iacono M, Baiamonte E, Lo Re R, Maggio A, Cavalieri V. An optimized procedure for preparation of conditioned medium from Wharton's jelly mesenchymal stromal cells isolated from umbilical cord. Front Mol Biosci 2023; 10:1273814. [PMID: 37854039 PMCID: PMC10580810 DOI: 10.3389/fmolb.2023.1273814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 09/20/2023] [Indexed: 10/20/2023] Open
Abstract
Cell-free therapy based on conditioned medium derived from mesenchymal stromal cells (MSCs) has gained attention in the field of protective and regenerative medicine. However, the exact composition and properties of MSC-derived conditioned media can vary greatly depending on multiple parameters, which hamper standardization. In this study, we have optimized a procedure for preparation of conditioned medium starting from efficient isolation, propagation and characterization of MSCs from human umbilical cord, using a culture medium supplemented with human platelet lysate as an alternative source to fetal bovine serum. Our procedure successfully maximizes the yield of viable MSCs that maintain canonical key features. Importantly, under these conditions, the compositional profile and biological effects elicited by the conditioned medium preparations derived from these MSC populations do not depend on donor individuality. Moreover, approximately 120 L of conditioned medium could be obtained from a single umbilical cord, which provides a suitable framework to produce industrial amounts of toxic-free conditioned medium with predictable composition.
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Affiliation(s)
- Santina Acuto
- Campus of Haematology Franco e Piera Cutino, Villa Sofia-Cervello Hospital, Palermo, Italy
| | - Melania Lo Iacono
- Campus of Haematology Franco e Piera Cutino, Villa Sofia-Cervello Hospital, Palermo, Italy
| | - Elena Baiamonte
- Campus of Haematology Franco e Piera Cutino, Villa Sofia-Cervello Hospital, Palermo, Italy
| | - Rosa Lo Re
- Campus of Haematology Franco e Piera Cutino, Villa Sofia-Cervello Hospital, Palermo, Italy
| | - Aurelio Maggio
- Campus of Haematology Franco e Piera Cutino, Villa Sofia-Cervello Hospital, Palermo, Italy
| | - Vincenzo Cavalieri
- Laboratory of Molecular Biology, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STeBiCeF), University of Palermo, Palermo, Italy
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Zhou AK, Jou E, Lu V, Zhang J, Chabra S, Abishek J, Wong E, Zeng X, Guo B. Using Pre-Clinical Studies to Explore the Potential Clinical Uses of Exosomes Secreted from Induced Pluripotent Stem Cell-Derived Mesenchymal Stem cells. Tissue Eng Regen Med 2023; 20:793-809. [PMID: 37651091 PMCID: PMC10519927 DOI: 10.1007/s13770-023-00557-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 05/09/2023] [Accepted: 05/16/2023] [Indexed: 09/01/2023] Open
Abstract
Recent studies of exosomes derived from mesenchymal stem cells (MSCs) have indicated high potential clinical applications in many diseases. However, the limited source of MSCs impedes their clinical research and application. Most recently, induced pluripotent stem cells (iPSCs) have become a promising source of MSCs. Exosome therapy based on iPSC-derived MSCs (iMSCs) is a novel technique with much of its therapeutic potential untapped. Compared to MSCs, iMSCs have proved superior in cell proliferation, immunomodulation, generation of exosomes capable of controlling the microenvironment, and bioactive paracrine factor secretion, while also theoretically eliminating the dependence on immunosuppression drugs. The therapeutic effects of iMSC-derived exosomes are explored in many diseases and are best studied in wound healing, cardiovascular disease, and musculoskeletal pathology. It is pertinent clinicians have a strong understanding of stem cell therapy and the latest advances that will eventually translate into clinical practice. In this review, we discuss the various applications of exosomes derived from iMSCs in clinical medicine.
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Affiliation(s)
- Andrew Kailin Zhou
- Addenbrookes Major Trauma Unit, Department of Trauma And Orthopaedics, Cambridge University Hospitals, Cambridge, UK
- Watford General Hospital, London, UK
| | - Eric Jou
- Addenbrookes Major Trauma Unit, Department of Trauma And Orthopaedics, Cambridge University Hospitals, Cambridge, UK
- School Of Clinical Medicine, University Of Cambridge, Cambridge, UK
| | - Victor Lu
- Addenbrookes Major Trauma Unit, Department of Trauma And Orthopaedics, Cambridge University Hospitals, Cambridge, UK
- School Of Clinical Medicine, University Of Cambridge, Cambridge, UK
| | - James Zhang
- Addenbrookes Major Trauma Unit, Department of Trauma And Orthopaedics, Cambridge University Hospitals, Cambridge, UK
- School Of Clinical Medicine, University Of Cambridge, Cambridge, UK
| | - Shirom Chabra
- School Of Clinical Medicine, University Of Cambridge, Cambridge, UK
| | | | | | - Xianwei Zeng
- Beijing Rehabilitation Hospital Affiliated to National Research Centre for Rehabilitation Technical Aids, Ministry of Civil Affairs of China, Beijing, China.
- Weifang People's Hospital, Weifang City, Shandong Province, China.
| | - Baoqiang Guo
- Department of Life Science, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, UK.
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He C, Yang C, Zeng Q, Liu Z, Wang F, Chen Q, Liu T. Umbilical cord-derived mesenchymal stem cells cultured in the MCL medium for aplastic anemia therapy. Stem Cell Res Ther 2023; 14:224. [PMID: 37649079 PMCID: PMC10470151 DOI: 10.1186/s13287-023-03417-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 07/18/2023] [Indexed: 09/01/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are a class of adult stem cells with self-renewal and multidirectional differentiation potential that may be a treatment for aplastic anemia (AA). METHOD Umbilical cord-derived MSCs were cultured in three media (Mesencult-XF, MCL, and StemPro MSC SFM CTS). HGF, PGE2, ANG-1, TGF-β1, IFN-γ, and TNF-α were detected using ELISA. The AA mouse model was built via post-irradiation lymphocyte infusion. After different treatments, routine blood, VEGF, and Tregs were detected every week. On day 28, all mice were killed, and their femurs were stained with HE. RESULTS Umbilical cord-derived MSCs cultured in the three media all conformed to the general characteristics of MSCs. HGF secreted by MSCs in the Mesencult-XF, and MCL was greater than that in the StemPro MSC SFM CTS; ANG-1 and TGF-β1 in the MCL were more than that in Mesencult-XF and StemPro MSC SFM CTS; PGE2 in the MCL and StemPro MSC SFM CTS was more than that in the Mesencult-XF. MSCs in the MCL and StemPro MSC SFM CTS inhibited IFN-γ and TNF-α more than those in the Mesencult-XF. The peripheral blood cell in the AA groups was at a low level while that in the MSC group recovered rapidly. The Treg ratio and VEGF level in the MSC group were higher than those in the AA group. The bone marrow (BM) recovered significantly after MSC infusion. CONCLUSION MSCs in the MCL were advantageous in supporting hematopoiesis and modulating immunity and had the potential for effective treatment of AA.
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Affiliation(s)
- Chuan He
- Department of Hematology and Institute of Hematology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chao Yang
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-Life Stem Cell Biotech Inc., 15 Jinquan Road, Chengdu, 610036, China
| | - Qiang Zeng
- Department of Hematology and Institute of Hematology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhigang Liu
- Department of Hematology and Institute of Hematology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Fangfang Wang
- Department of Hematology and Institute of Hematology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Qiang Chen
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-Life Stem Cell Biotech Inc., 15 Jinquan Road, Chengdu, 610036, China.
| | - Ting Liu
- Department of Hematology and Institute of Hematology, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Yea JH, Kim Y, Jo CH. Comparison of mesenchymal stem cells from bone marrow, umbilical cord blood, and umbilical cord tissue in regeneration of a full-thickness tendon defect in vitro and in vivo. Biochem Biophys Rep 2023; 34:101486. [PMID: 37234487 PMCID: PMC10206173 DOI: 10.1016/j.bbrep.2023.101486] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 04/15/2023] [Accepted: 05/11/2023] [Indexed: 05/28/2023] Open
Abstract
Although mesenchymal stem cells (MSCs) can be obtained from various tissues such as bone marrow (BM), umbilical cord blood (UCB) and umbilical cord tissue (UC), the comparative efficacy of each MSC in tendon regeneration is unknown. Therefore, we investigated the efficacy of MSCs isolated from three different sources on tendon regeneration after injury. We evaluated the potential of BM-, UCB- and UC-MSC to differentiate into tendon-like cells in tensioned three-dimensional construct (T-3D) using gene and histological analysis. In animal experiments, full-thickness tendon defect (FTD) was created in supraspinatus of rats, and injected with Saline and BM-, UCB- and UC-MSC. After two and four weeks, histological evaluations were performed. After inducing tenogenic differentiation, the gene expression of scleraxis, mohawk, type I collagen and tenascin-C was upregulated by 3.12-, 5.92-, 6.01- and 1.61-fold respectively and formation of tendon-like matrix was increased 4.22-fold in UC-MSC compared to BM-MSC in T-3D. In animal experiments, the total degeneration score was lower in the UC-MSC group than in BM-MSC group at both weeks. In heterotopic matrix formation, glycosaminoglycan-rich area was reduced in the UC-MSC group, whereas area was larger in the BM-MSC group than in Saline group at four weeks. In conclusion, UC-MSC is superior to other MSCs in differentiating into tendon-like lineage cells and forming a well-organized tendon-like matrix under T-3D conditions. UC-MSC enhances regeneration of FTD in terms of histological properties compared to BM- and UCB-MSC.
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Affiliation(s)
- Ji-Hye Yea
- Department of Pathology, Johns Hopkins University, Baltimore, MD, USA
| | - Yeasol Kim
- Department of Translational Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Department of Orthopedic Surgery, SMG-SNU Boramae Medical Center, Seoul National University College of Medicine, Seoul, South Korea
| | - Chris H. Jo
- Department of Translational Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Department of Orthopedic Surgery, SMG-SNU Boramae Medical Center, Seoul National University College of Medicine, Seoul, South Korea
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29
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Çetin EA, Babayiğit EH, Özdemir AY, Erfen Ş, Onur MA. Investigation of UV-treated mesenchymal stem cells in an in vitro wound model. In Vitro Cell Dev Biol Anim 2023:10.1007/s11626-023-00772-4. [PMID: 37296290 DOI: 10.1007/s11626-023-00772-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 05/09/2023] [Indexed: 06/12/2023]
Abstract
This study examines the effects of ultraviolet-induced adipose tissue-derived mesenchymal stem cells and their supernatants on wound healing regarding cell viability, percentage of wound healing, released cytokine, and growth factors. It has been reported in previous studies that mesenchymal stem cells are resistant to ultraviolet light and have a protective effect on skin cells against ultraviolet-induced damage. At the same time, there are many studies in the literature about the positive effects of cytokines and growth factors secreted by mesenchymal stem cells. Based on this information, the effects of ultraviolet-induced adipose-derived stem cells and supernatants containing their secreted cytokines and growth factors on an in vitro two-dimensional wound model created with two different cell lines were investigated in this study. It was determined from the results that the highest cell viability and the least apoptotic staining were 100 mJ in mesenchymal stem cells (**p < 0.01). Furthermore, analysis of cytokines and growth factors collected from supernatants also supported 100 mJ as the optimal ultraviolet dose. It was observed that cells treated with ultraviolet and their supernatants significantly increased cell viability and wound-healing rate over time compared to other groups. In conclusion, with this study, it has been shown that adipose-derived stem cells exposed to ultraviolet light can have an important use in wound healing, both with their potential and with the more cytokines and growth factors they secrete. However, further analysis and animal experiments should be performed before clinical use.
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Affiliation(s)
- Esin Akbay Çetin
- Department of Biology, Faculty of Science, Hacettepe University, 06800, Ankara, Turkey.
| | - Elif Hatice Babayiğit
- Department of Biology, Faculty of Science, Hacettepe University, 06800, Ankara, Turkey
| | - Alp Yiğit Özdemir
- Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Şebnem Erfen
- Department of Biology, Faculty of Science, Hacettepe University, 06800, Ankara, Turkey
| | - Mehmet Ali Onur
- Department of Biology, Faculty of Science, Hacettepe University, 06800, Ankara, Turkey
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30
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Rosner M, Horer S, Feichtinger M, Hengstschläger M. Multipotent fetal stem cells in reproductive biology research. Stem Cell Res Ther 2023; 14:157. [PMID: 37287077 DOI: 10.1186/s13287-023-03379-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 05/16/2023] [Indexed: 06/09/2023] Open
Abstract
Due to the limited accessibility of the in vivo situation, the scarcity of the human tissue, legal constraints, and ethical considerations, the underlying molecular mechanisms of disorders, such as preeclampsia, the pathological consequences of fetomaternal microchimerism, or infertility, are still not fully understood. And although substantial progress has already been made, the therapeutic strategies for reproductive system diseases are still facing limitations. In the recent years, it became more and more evident that stem cells are powerful tools for basic research in human reproduction and stem cell-based approaches moved into the center of endeavors to establish new clinical concepts. Multipotent fetal stem cells derived from the amniotic fluid, amniotic membrane, chorion leave, Wharton´s jelly, or placenta came to the fore because they are easy to acquire, are not associated with ethical concerns or covered by strict legal restrictions, and can be banked for autologous utilization later in life. Compared to adult stem cells, they exhibit a significantly higher differentiation potential and are much easier to propagate in vitro. Compared to pluripotent stem cells, they harbor less mutations, are not tumorigenic, and exhibit low immunogenicity. Studies on multipotent fetal stem cells can be invaluable to gain knowledge on the development of dysfunctional fetal cell types, to characterize the fetal stem cells migrating into the body of a pregnant woman in the context of fetomaternal microchimerism, and to obtain a more comprehensive picture of germ cell development in the course of in vitro differentiation experiments. The in vivo transplantation of fetal stem cells or their paracrine factors can mediate therapeutic effects in preeclampsia and can restore reproductive organ functions. Together with the use of fetal stem cell-derived gametes, such strategies could once help individuals, who do not develop functional gametes, to conceive genetically related children. Although there is still a long way to go, these developments regarding the usage of multipotent fetal stem cells in the clinic should continuously be accompanied by a wide and detailed ethical discussion.
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Affiliation(s)
- Margit Rosner
- Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria
| | - Stefanie Horer
- Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria
| | | | - Markus Hengstschläger
- Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria.
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31
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Nowroozzadeh MH, Ghazanfari S, Sanie-Jahromi F. Human Wharton's Jelly Mesenchymal Stem Cell Secretome Modifies the Processes of Neuroprotection and Epithelial-Mesenchymal Transition in Retinal Pigment Epithelium at Transcriptional Level. Mol Biol Rep 2023:10.1007/s11033-023-08496-0. [PMID: 37217618 DOI: 10.1007/s11033-023-08496-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 04/28/2023] [Indexed: 05/24/2023]
Abstract
BACKGROUND Retinal pigment epithelium (RPE) cells are potential targets for treating retinal detachment (RD) and proliferative vitreoretinopathy (PVR), considering the importance of neuroprotection and epithelial-mesenchymal transition (EMT) of RPE in these conditions. This study investigated the effect of human Wharton's jelly mesenchymal stem cell secretome (WJMSC-S) on the expression of genes involved in both neuroprotection and EMT in RPE cells in vitro (TRKB, MAPK, PI3K, BDNF, and NGF). METHODS RPE cells from passages 5-7 were treated with WJMSC-S (or the vehicle culture medium as control) for 24 h at 37◦C and subsequently subjected to RNA extraction and cDNA synthesis. Gene expression level was evaluated using real-time PCR in the treated versus control cells. RESULTS The results of our study showed that WJMSC-S led to a significant downregulation in three out of five studied gene expression (MAPK, TRKB, and NGF), and simultaneously, remarkably upregulated the expression of the BDNF gene. CONCLUSIONS According to the present data, WJMSC-S can affect the EMT and neuroprotection processes at the mRNA level by suppressing EMT and promoting neuroprotection in RPE cells. This finding may have positive clinical implications in the context of RD and PVR.
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Affiliation(s)
- M Hossein Nowroozzadeh
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Zand Boulevard, Poostchi Street, Shiraz, Iran
| | - Shiva Ghazanfari
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Zand Boulevard, Poostchi Street, Shiraz, Iran
| | - Fatemeh Sanie-Jahromi
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Zand Boulevard, Poostchi Street, Shiraz, Iran.
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32
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Guan Z, Zhang J, Jiang N, Tian M, Wang H, Liang B. Efficacy of mesenchymal stem cell therapy in rodent models of radiation-induced xerostomia and oral mucositis: a systematic review. Stem Cell Res Ther 2023; 14:82. [PMID: 37046350 PMCID: PMC10099931 DOI: 10.1186/s13287-023-03301-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 03/27/2023] [Indexed: 04/14/2023] Open
Abstract
BACKGROUND Radiation-induced xerostomia and oral mucositis are serious complications of radiation therapy for head and neck cancers. Current treatment options have limited efficacy. Mesenchymal stem cell (MSC) therapy has shown promising results in supporting the restoration of glandular secretion function and the regeneration of damaged tissues. This study aim to (1) assess the quality of evidence for MSCs treatment in rodent models of radiation-induced oral complications and (2) determine whether MSCs can improve the therapeutic effect of radiation-induced oral mucositis. METHODS Intervention studies using MSCs in rodent models were comprehensively retrieved in the Pubmed, Medline, Embase, Web of Science, and Cochrane library databases on June 1, 2022. The quality of all in vivo experiments was assessed using SYRCLE, and this article is written following the PRISMA guidelines. RESULTS A total of 12 studies were included in this systematic review. The study found that in animal models of radiation-induced xerostomia, MSCs could increase salivary protein secretion, improve SFR, shorten the salivary lag time, anti-apoptosis, etc. In animal models of radiation-induced oral mucositis, MSCs improve the micromorphology and macromorphology of RIOM. Moreover, the effect of MSCs on the modification of ulcer duration and latency may be related to the time of MSCs transplantation but further studies are needed. CONCLUSION The results of our systematic review suggest that MSCs appeared to be effective in the treatment of radiation-induced xerostomia and oral mucositis.
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Affiliation(s)
- Zirui Guan
- The Second Hospital of Jilin University, Changchun City, 130022, Jilin Province, People's Republic of China
| | - Jiaxin Zhang
- School of Nursing, Jilin University, Changchun City, 130021, Jilin Province, People's Republic of China
| | - Nan Jiang
- School of Nursing, Jilin University, Changchun City, 130021, Jilin Province, People's Republic of China
| | - Mingyan Tian
- The Second Hospital of Jilin University, Changchun City, 130022, Jilin Province, People's Republic of China
| | - Hongyong Wang
- The Second Hospital of Jilin University, Changchun City, 130022, Jilin Province, People's Republic of China.
| | - Bing Liang
- School of Nursing, Jilin University, Changchun City, 130021, Jilin Province, People's Republic of China.
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Arangath A, Duffy N, Alexandrov S, James S, Neuhaus K, Murphy M, Leahy M. Nanosensitive optical coherence tomography for detecting structural changes in stem cells. BIOMEDICAL OPTICS EXPRESS 2023; 14:1411-1427. [PMID: 37078060 PMCID: PMC10110307 DOI: 10.1364/boe.485082] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 02/04/2023] [Accepted: 02/19/2023] [Indexed: 05/03/2023]
Abstract
Mesenchymal stromal cells (MSCs) are adult stem cells that have been widely investigated for their potential to regenerate damaged and diseased tissues. Multiple pre-clinical studies and clinical trials have demonstrated a therapeutic response following treatment with MSCs for various pathologies, including cardiovascular, neurological and orthopaedic diseases. The ability to functionally track cells following administration in vivo is pivotal to further elucidating the mechanism of action and safety profile of these cells. Effective monitoring of MSCs and MSC-derived microvesicles requires an imaging modality capable of providing both quantitative and qualitative readouts. Nanosensitive optical coherence tomography (nsOCT) is a recently developed technique that detects nanoscale structural changes within samples. In this study, we demonstrate for the first time, the capability of nsOCT to image MSC pellets following labelling with different concentrations of dual plasmonic gold nanostars. We show that the mean spatial period of MSC pellets increases following the labelling with increasing concentrations of nanostars. Additionally, with the help of extra time points and a more comprehensive analysis, we further improved the understanding of the MSC pellet chondrogenesis model. Despite the limited penetration depth (similar to conventional OCT), the nsOCT is highly sensitive in detecting structural alterations at the nanoscale, which may provide crucial functional information about cell therapies and their modes of action.
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Affiliation(s)
- Anand Arangath
- Tissue Optics and Microcirculation Imaging Facility, Physics, School of Natural Sciences, University of Galway, Galway, Ireland
| | - Niamh Duffy
- Regenerative Medicine Institute, University of Galway, Galway, Ireland
| | - Sergey Alexandrov
- Tissue Optics and Microcirculation Imaging Facility, Physics, School of Natural Sciences, University of Galway, Galway, Ireland
| | - Soorya James
- Tissue Optics and Microcirculation Imaging Facility, Physics, School of Natural Sciences, University of Galway, Galway, Ireland
| | - Kai Neuhaus
- Casey Eye Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Mary Murphy
- Regenerative Medicine Institute, University of Galway, Galway, Ireland
| | - Martin Leahy
- Tissue Optics and Microcirculation Imaging Facility, Physics, School of Natural Sciences, University of Galway, Galway, Ireland
- The Institute of Photonic Sciences (ICFO), Barcelona, Spain
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Umer A, Khan N, Greene DL, Habiba UE, Shamim S, Khayam AU. The Therapeutic Potential of Human Umbilical Cord Derived Mesenchymal Stem Cells for the Treatment of Premature Ovarian Failure. Stem Cell Rev Rep 2023; 19:651-666. [PMID: 36520408 PMCID: PMC10070285 DOI: 10.1007/s12015-022-10493-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/10/2022] [Indexed: 12/23/2022]
Abstract
Premature ovarian failure (POF) affects 1% of women under 40, leading to infertility. The clinical symptoms of the POF include hypoestrogenism, lack of mature follicles, hypergonadotropinism, and amenorrhea. POF can be caused due to genetic defects, autoimmune illnesses, and environmental factors. The conventional treatment of POF remains a limited success rate. Therefore, an innovative treatment strategy like the regeneration of premature ovaries by using human umbilical cord mesenchymal stem cells (hUC-MSCs) can be a choice. To summarize all the theoretical frameworks for additional research and clinical trials, this review article highlights all the results, pros, and cons of the hUC-MSCs used to treat POF. So far, the data shows promising results regarding the treatment of POF using hUC-MSCs. Several properties like relatively low immunogenicity, multipotency, multiple origins, affordability, convenience in production, high efficacy, and donor/recipient friendliness make hUC-MSCs a good choice for treating basic POF. It has been reported that hUC-MSCs impact and enhance all stages of injured tissue regeneration by concurrently stimulating numerous pathways in a paracrine manner, which are involved in the control of ovarian fibrosis, angiogenesis, immune system modulation, and apoptosis. Furthermore, some studies demonstrated that stem cell treatment could lead to hormone-level restoration, follicular activation, and functional restoration of the ovaries. Therefore, all the results in hand regarding the use of hUC-MSCs for the treatment of POF encourage researchers for further clinical trials, which will overcome the ongoing challenges and make this treatment strategy applicable to the clinic in the near future.
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Affiliation(s)
- Amna Umer
- R3 Medical and Research Institute Pvt. Ltd, Jahangir Multiplex, H-13 Sector, Islamabad, 44000, Pakistan
| | - Nasar Khan
- R3 Medical and Research Institute Pvt. Ltd, Jahangir Multiplex, H-13 Sector, Islamabad, 44000, Pakistan.
- R3 Medical Research LLC, 10045 East Dynamite Boulevard Suite 260, Scottsdale, AZ, 85262, USA.
| | - David Lawrence Greene
- R3 Medical and Research Institute Pvt. Ltd, Jahangir Multiplex, H-13 Sector, Islamabad, 44000, Pakistan
- R3 Medical Research LLC, 10045 East Dynamite Boulevard Suite 260, Scottsdale, AZ, 85262, USA
| | - Umm E Habiba
- R3 Medical and Research Institute Pvt. Ltd, Jahangir Multiplex, H-13 Sector, Islamabad, 44000, Pakistan
| | - Sabiha Shamim
- R3 Medical and Research Institute Pvt. Ltd, Jahangir Multiplex, H-13 Sector, Islamabad, 44000, Pakistan
| | - Asma Umer Khayam
- Department of Biochemistry, Quaid e Azam University, Islamabad, 44000, Pakistan
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Mesenchymal Stem Cells in Acquired Aplastic Anemia: The Spectrum from Basic to Clinical Utility. Int J Mol Sci 2023; 24:ijms24054464. [PMID: 36901900 PMCID: PMC10003043 DOI: 10.3390/ijms24054464] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 02/17/2023] [Accepted: 02/21/2023] [Indexed: 03/12/2023] Open
Abstract
Aplastic anemia (AA), a rare but potentially life-threatening disease, is a paradigm of bone marrow failure syndromes characterized by pancytopenia in the peripheral blood and hypocellularity in the bone marrow. The pathophysiology of acquired idiopathic AA is quite complex. Mesenchymal stem cells (MSCs), an important component of the bone marrow, are crucial in providing the specialized microenvironment for hematopoiesis. MSC dysfunction may result in an insufficient bone marrow and may be associated with the development of AA. In this comprehensive review, we summarized the current understanding about the involvement of MSCs in the pathogenesis of acquired idiopathic AA, along with the clinical application of MSCs for patients with the disease. The pathophysiology of AA, the major properties of MSCs, and results of MSC therapy in preclinical animal models of AA are also described. Several important issues regarding the clinical use of MSCs are discussed finally. With evolving knowledge from basic studies and clinical applications, we anticipate that more patients with the disease can benefit from the therapeutic effects of MSCs in the near future.
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Gao S, Chen B, Zhu Z, Du C, Zou J, Yang Y, Huang W, Liao J. PI3K-Akt signaling regulates BMP2-induced osteogenic differentiation of mesenchymal stem cells (MSCs): A transcriptomic landscape analysis. Stem Cell Res 2023; 66:103010. [PMID: 36580886 DOI: 10.1016/j.scr.2022.103010] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/30/2022] [Accepted: 12/22/2022] [Indexed: 12/24/2022] Open
Abstract
Bone morphogenetic protein 2 (BMP2) effectively induced mesenchymal stem cells (MSCs) osteogenic differentiation hold great potential for bone tissue engineering. However, a global mechanistic view of BMP2-induced osteogenic differentiation of MSCs remains to be fully elucidated. Here, human umbilical cord-derived MSCs (UC-MSCs) were induced with BMP2, three days and five days later, total RNA were extracted and subjected to RNA-sequencing (RNA-Seq) followed with bioinformatic analysis. Osteogenic differentiation abilities were evaluated with Alkaline phosphatase (ALP) staining and osteogenic differentiation marker expression at both mRNA and protein levels. We identified that adenoviral vectors effectively transduced in UC-MSCs and expressed BMP2 in high efficiency. Both on day 3 and day 5, differentially expressed genes (DEGs) were highly enriched in PI3K-Akt signaling pathway. As for the common DEGs among total BMP2 group vs control group, BMP2 (day 3) versus control (day 3) and BMP2 (day 5) versus control (day 5), there were 105 DGEs and highly enriched in PI3K-Akt signaling pathway. Finally, we found that PI3K-Akt signaling inhibitor dramatically inhibited BMP2-iduced osteogenic differentiation of UC-MSCs. We firstly identified that PI3K-Akt signaling pathway plays a pivotal role in BMP2-induced osteogenic differentiation of MSCs, which may apply a new perspective for BMP2 based bone tissue engineering.
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Affiliation(s)
- Shengqiang Gao
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Orthopedic Research Laboratory, Chongqing Medical University, Chongqing 400016, China
| | - Bowen Chen
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Orthopedic Research Laboratory, Chongqing Medical University, Chongqing 400016, China
| | - Zhenglin Zhu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Orthopedic Research Laboratory, Chongqing Medical University, Chongqing 400016, China
| | - Chengcheng Du
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Orthopedic Research Laboratory, Chongqing Medical University, Chongqing 400016, China
| | - Jing Zou
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Orthopedic Research Laboratory, Chongqing Medical University, Chongqing 400016, China
| | - Yaji Yang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Orthopedic Research Laboratory, Chongqing Medical University, Chongqing 400016, China
| | - Wei Huang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Orthopedic Research Laboratory, Chongqing Medical University, Chongqing 400016, China.
| | - Junyi Liao
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Orthopedic Research Laboratory, Chongqing Medical University, Chongqing 400016, China.
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Tian G, Liu C, Wang H, Yu Z, Huang J, Gong Q, Zhang D, Cong H. Human umbilical cord mesenchymal stem cells prevent glucocorticoid-induced osteonecrosis of the femoral head by promoting angiogenesis. J Plast Surg Hand Surg 2023; 57:71-77. [PMID: 34570665 DOI: 10.1080/2000656x.2021.1981352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
The impairment of angiogenesis is an outstanding pathogenic characteristic of glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH). Human umbilical cord mesenchymal stem cells (hUC-MSCs) have been used in several diseases models, which were reported to be involved in the angiogenesis. However, whether hUC-MSCs suppress the GC-induced ONFH via promoting angiogenesis is still unclear. hUC-MSCs were isolated from the Wharton's jelly using the explant culture method. A GC-induced ONFH model was established in vitro and in vivo. The angiogenesis, proliferation and migration ability of HMECs were determined using the tube-forming, CCK-8, transwell and scratching assays in vitro. The protective role of hUC-MSCs in GC-induced ONFH was evaluated using micro-CT scanning and histological, immunohistochemical (IHC) and Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assays in vivo. The results showed that hUC-MSCs treatment improved the tube-forming, proliferation and migration ability of HMECs in vitro. Moreover, hUC-MSCs treatment enhanced the integrity of trabecular bone of the femoral head, and the tube-forming ability in vivo. hUC-MSCs prevent the femoral head against necrosis and damage caused by GCs though promoting angiogenesis.
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Affiliation(s)
- Gang Tian
- Department of Orthopedics, Weihai Central Hospital, Affiliated to Qingdao University & Qingdao University, Weihai, China
| | - Chuanjie Liu
- Weihai Key Laboratory of Autoimmunity & Central Laboratory, Weihai Central Hospital, Affiliated to Qingdao University & Qingdao University, Weihai, China
| | - Haitao Wang
- Department of Trauma Surgery, Weihai Central Hospital Affiliated to Qingdao University, Weihai, China
| | - Zhiping Yu
- Department of Sports Medicine, Weihai Central Hospital Affiliated to Qingdao University, Weihai, China
| | - Jian Huang
- Department of Sports Medicine, Limin Hospital, Weihai City Central Hospital, Weihai, China
| | - Qi Gong
- Weihai Key Laboratory of Autoimmunity & Central Laboratory, Weihai Central Hospital, Affiliated to Qingdao University & Qingdao University, Weihai, China
| | - Daoqiang Zhang
- Weihai Key Laboratory of Autoimmunity & Central Laboratory, Weihai Central Hospital, Affiliated to Qingdao University & Qingdao University, Weihai, China
| | - Haibo Cong
- Department of Orthopedics, Weihai Central Hospital, Affiliated to Qingdao University & Weihai Key Laboratory of Autoimmunity, Qingdao University, Weihai, China
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38
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Alqahtani S, Butcher MC, Ramage G, Dalby MJ, McLean W, Nile CJ. Acetylcholine Receptors in Mesenchymal Stem Cells. Stem Cells Dev 2023; 32:47-59. [PMID: 36355611 DOI: 10.1089/scd.2022.0201] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are well known for their regenerative potential. Even though the ability of MSCs to proliferate and differentiate has been studied extensively, there remains much to learn about the signaling mechanisms and pathways that control proliferation and influence the differentiation phenotype. In recent years, there has been growing evidence for the utility of non-neuronal cholinergic signaling systems and that acetylcholine (ACh) plays an important ubiquitous role in cell-to-cell communication. Indeed, cholinergic signaling is hypothesized to occur in stem cells and ACh synthesis, as well as in ACh receptor (AChR) expression, has been identified in several stem cell populations, including MSCs. Furthermore, AChRs have been found to influence MSC regenerative potential. In humans, there are two major classes of AChRs, muscarinic AChRs and nicotinic AChRs, with each class possessing several subtypes or subunits. In this review, the expression and function of AChRs in different types of MSC are summarized with the aim of highlighting how AChRs play a pivotal role in regulating MSC regenerative function.
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Affiliation(s)
- Saeed Alqahtani
- School of Medicine Dentistry and Nursing and University of Glasgow, Glasgow, United Kingdom
| | - Mark C Butcher
- School of Medicine Dentistry and Nursing and University of Glasgow, Glasgow, United Kingdom
| | - Gordon Ramage
- School of Medicine Dentistry and Nursing and University of Glasgow, Glasgow, United Kingdom
| | - Matthew J Dalby
- School of Molecular Biosciences, University of Glasgow, Glasgow, United Kingdom
| | - William McLean
- School of Medicine Dentistry and Nursing and University of Glasgow, Glasgow, United Kingdom
| | - Christopher J Nile
- Faculty of Medical Sciences, School of Dental Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
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Mesenchymal stem cell therapy: A review of clinical trials for multiple sclerosis. Regen Ther 2022; 21:201-209. [PMID: 36092509 PMCID: PMC9420954 DOI: 10.1016/j.reth.2022.07.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 07/02/2022] [Accepted: 07/15/2022] [Indexed: 11/22/2022] Open
Abstract
Multiple sclerosis (MS) is a disease of the central nervous system (CNS) that is the result of the body's own immune cells being auto-reactive to the myelin regions of the body as if these regions were foreign antigens. This demyelination process is damaging to the electrical conductivity of neurons. The current medicines are only capable of fighting off the symptoms of the disease, but not the disease itself. Specialized stem cells, known as mesenchymal stem cells (MSCs), seem to be the candidate therapy to get rid of MS. MSCs can be isolated from multiple sources of the person's body, and even from the umbilical cord (UC) and placenta of a donor. These cells have anti-inflammatory effects so they can target the overactivity and self-antigen attacks by T cells and macrophages; this immune system overactivity is characteristic of MS. MSCs show the ability to locate into brain lesions when injected and thus can compensate for the loss of the brain function by differentiating into neuronal precursor cells and glial cells. The author has listed tables of clinical trials that have utilized MSCs from different sources, along with the years and the phase of study completed for each trial. The consensus is that these cells work on inhibiting CD4+ and CD8+ T cell activation, T regulatory cells (Tregs), and macrophage switch into the auto-immune phenotype. The best source of MSCs seems to be the UC due to the easiness of extraction, the noninvasive method of collection, their higher expansion ability and more powerful immune-modulating properties compared to other locations in the body. Studies showed there was a significant decline of mRNA expression of several cytokines after the administration of MSCs derived from the UC (UCMSCs). Other researchers were able to repair the defects of Tregs in MS patients by co-culturing Tregs from these patients with UCMSCs, which decreased the production of the pro-inflammatory cytokine IFN γ, and also suggested a strong link between Tregs lack of functionality in MS patients with the pathogenesis of the disease.
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Zhang L, Pei C, Hou D, Yang G, Yu D. Inhibition of Cerebral Ischemia/Reperfusion Injury by MSCs-Derived Small Extracellular Vesicles in Rodent Models: A Systematic Review and Meta-Analysis. Neural Plast 2022; 2022:3933252. [PMID: 36338577 PMCID: PMC9633211 DOI: 10.1155/2022/3933252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 09/17/2022] [Indexed: 01/03/2025] Open
Abstract
Small extracellular vesicles (sEVs) secreted by mesenchymal stem cells (MSCs) have shown great therapeutic potential in cerebral ischemia-reperfusion injury (CIRI). In this study, we firstly performed a systematic review to evaluate the efficacy of MSCs-derived sEV for experimental cerebral ischemia/reperfusion injury. 24 studies were identified by searching 8 databases from January 2012 to August 2022. The methodological quality was assessed by using the SYRCLE 's risk of bias tool for animal studies. All the data were analyzed using RevMan 5.3 software. As a result, the score of study quality ranged from 3 to 9 in a total of ten points. Meta-analyses showed that MSCs-derived sEVs could effectively alleviate neurological impairment scores, reduced the volume of cerebral infarction and brain water content, and attenuated neuronal apoptosis. Additionally, the possible mechanisms of MSCs-derived sEVs for attenuating neuronal apoptosis were inhibiting microglia-mediated neuroinflammation. Thus, MSCs-derived sEVs might be regarded as a novel insight for cerebral ischemic stroke. However, further mechanistic studies, therapeutic safety, and clinical trials are required. Systematic review registration. PROSPERO CRD42022312227.
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Affiliation(s)
- Lei Zhang
- Department of Neurology, Affiliated Haikou Hospital of Xiangya School of Medicine, Central South University, Haikou 570208, China
| | - Chaoying Pei
- Department of Neurology, Affiliated Haikou Hospital of Xiangya School of Medicine, Central South University, Haikou 570208, China
| | - Dan Hou
- Department of Neurology, Affiliated Haikou Hospital of Xiangya School of Medicine, Central South University, Haikou 570208, China
| | - Guoshuai Yang
- Department of Neurology, Affiliated Haikou Hospital of Xiangya School of Medicine, Central South University, Haikou 570208, China
| | - Dan Yu
- Department of Neurology, Affiliated Haikou Hospital of Xiangya School of Medicine, Central South University, Haikou 570208, China
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Bunnell BA, Martin EC, Matossian MD, Brock CK, Nguyen K, Collins-Burow B, Burow ME. The effect of obesity on adipose-derived stromal cells and adipose tissue and their impact on cancer. Cancer Metastasis Rev 2022; 41:549-573. [PMID: 35999486 DOI: 10.1007/s10555-022-10063-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 08/16/2022] [Indexed: 11/24/2022]
Abstract
The significant increase in the incidence of obesity represents the next global health crisis. As a result, scientific research has focused on gaining deeper insights into obesity and adipose tissue biology. As a result of the excessive accumulation of adipose tissue, obesity results from hyperplasia and hypertrophy within the adipose tissue. The functional alterations in the adipose tissue are a confounding contributing factor to many diseases, including cancer. The increased incidence and aggressiveness of several cancers, including colorectal, postmenopausal breast, endometrial, prostate, esophageal, hematological, malignant melanoma, and renal carcinomas, result from obesity as a contributing factor. The increased morbidity and mortality of obesity-associated cancers are attributable to increased hormones, adipokines, and cytokines produced by the adipose tissue. The increased adipose tissue levels observed in obese patients result in more adipose stromal/stem cells (ASCs) distributed throughout the body. ASCs have been shown to impact cancer progression in vitro and in preclinical animal models. ASCs influence tumor biology via multiple mechanisms, including the increased recruitment of ASCs to the tumor site and increased production of cytokines and growth factors by ASCs and other cells within the tumor stroma. Emerging evidence indicates that obesity induces alterations in the biological properties of ASCs, subsequently leading to enhanced tumorigenesis and metastasis of cancer cells. As the focus of this review is the interaction and impact of ASCs on cancer, the presentation is limited to preclinical data generated on cancers in which there is a demonstrated role for ASCs, such as postmenopausal breast, colorectal, prostate, ovarian, multiple myeloma, osteosarcoma, cervical, bladder, and gastrointestinal cancers. Our group has investigated the interactions between obesity and breast cancer and the mechanisms that regulate ASCs and adipocytes in these different contexts through interactions between cancer cells, immune cells, and other cell types present in the tumor microenvironment (TME) are discussed. The reciprocal and circular feedback loop between obesity and ASCs and the mechanisms by which ASCs from obese patients alter the biology of cancer cells and enhance tumorigenesis will be discussed. At present, the evidence for ASCs directly influencing human tumor growth is somewhat limited, though recent clinical studies suggest there may be some link.
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Affiliation(s)
- Bruce A Bunnell
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, 76107, USA.
| | - Elizabeth C Martin
- Department of Biological and Agricultural Engineering, Louisiana State University, Baton Rouge, LA, USA
| | - Margarite D Matossian
- Department of Microbiology, Immunology and Genetics, University of Chicago, IL, Chicago, USA
| | - Courtney K Brock
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Khoa Nguyen
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Bridgette Collins-Burow
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Matthew E Burow
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
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42
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Luo Q, Tang Y, Jiang Z, Bao H, Fu Q, Zhang H. hUCMSCs reduce theca interstitial cells apoptosis and restore ovarian function in premature ovarian insufficiency rats through regulating NR4A1-mediated mitochondrial mechanisms. Reprod Biol Endocrinol 2022; 20:125. [PMID: 35986315 PMCID: PMC9389823 DOI: 10.1186/s12958-022-00992-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 08/03/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Human umbilical cord mesenchymal stem cells (hUCMSCs, retrospectively registered) have a lot of promise for treating theca interstitial cells(TICs) dysfunction in premature ovarian insufficiency (POI). The mechanisms, however, are still unknown. METHODS To examine the therapeutic and find the cause, we used both in vivo cisplatin-induced POI rat model and in vitro TICs model. HUCMSCs were injected into the tail veins of POI rats in an in vivo investigation. Then, using ELISA, HE staining, TUNEL apoptosis test kit, immunohistochemistry and western blot, researchers examined hormonal levels, ovarian morphology, TICs apoptosis, NR4A1 and Cyp17a1 in response to cisplatin treatment and hUCMSCs. TICs were obtained from the ovaries of rats and treated with the cisplatin, hUCMSCs supernatant, and the antagonist of NR4A1--DIM-C-pPhOH. ELISA, immunofluorescence, flow cytometry, JC-1 labeling and western blot analysis were used to detect T levels, Cyp17a1, NR4A1, and the anti-apoptotic protein Bcl-2, as well as pro-apoptotic proteins Bax, caspase-9, caspase-3, and cytochrome C(cytc). RESULTS We discovered that hUCMSCs restored the ovarian function, particularly TICs function based on measures of Cyp17a1 and T expression. NR4A1 was found in ovarian TICs of each group and NR4A1 expression was lower in the POI rats but higher following hUCMSCs therapy. The apoptosis of TICs generated by cisplatin was reduced after treatment with hUCMSCs. In vitro, NR4A1 was expressed in the nucleus of TICs, and NR4A1 as well as phospho-NR4A1 were decreased, following the apoptosis of TICs was emerged after cisplatin treatment. Interestingly, the localization of NR4A1 was translocated from the nucleus to the cytoplasm due to cisplatin. HUCMSCs were able to boost NR4A1 and phospho-NR4A1 expression while TICs' apoptosis and JC-1 polymorimonomor fluorescence ratios reduced. Furthermore, Bcl-2 expression dropped following cisplatin treatment, whereas Bax, cytc, caspase-9, and caspase-3 expression rose; however, hUCMSCs treatment reduced their expression. In addition, DIM-C-pPhOH had no effect on the NR4A1 expression, but it did increase the expression of apoptosis-related factors such as Bax, cytc, caspase-9, and caspase-3, causing the apoptosis of TICs. CONCLUSIONS These data show that hUCMSCs therapy improves ovarian function in POI rats by inhibiting TICs apoptosis through regulating NR4A1 -mediated mitochondrial mechanisms.
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Affiliation(s)
- Qianqian Luo
- Xu Rongxiang Regenerative Medicine Research Center, Binzhou Medical University, Yantai, 264003, Shandong, China
- Basic Medical College, Binzhou Medical University, Yantai, 264003, China
| | - Yu Tang
- Basic Medical College, Binzhou Medical University, Yantai, 264003, China
| | - Zhonglin Jiang
- Xu Rongxiang Regenerative Medicine Research Center, Binzhou Medical University, Yantai, 264003, Shandong, China
- Basic Medical College, Binzhou Medical University, Yantai, 264003, China
| | - Hongchu Bao
- Department of Clinical Medicine, Yantai Yuhuangding Hospital, Yantai, 264000, China
| | - Qiang Fu
- School of Pharmacology, Institute of Aging Medicine, Binzhou Medical University, Yantai, 264003, China.
| | - Hongqin Zhang
- Xu Rongxiang Regenerative Medicine Research Center, Binzhou Medical University, Yantai, 264003, Shandong, China.
- Basic Medical College, Binzhou Medical University, Yantai, 264003, China.
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Wright A, Snyder OL, Christenson LK, He H, Weiss ML. Effect of Pre-Processing Storage Condition of Cell Culture-Conditioned Medium on Extracellular Vesicles Derived from Human Umbilical Cord-Derived Mesenchymal Stromal Cells. Int J Mol Sci 2022; 23:ijms23147716. [PMID: 35887064 PMCID: PMC9320900 DOI: 10.3390/ijms23147716] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/04/2022] [Accepted: 07/11/2022] [Indexed: 02/04/2023] Open
Abstract
EVs can be isolated from a conditioned medium derived from mesenchymal stromal cells (MSCs), yet the effect of the pre-processing storage condition of the cell culture-conditioned medium prior to EV isolation is not well-understood. Since MSCs are already in clinical trials, the GMP-grade of the medium which is derived from their manufacturing might have the utility for preclinical testing, and perhaps, for clinical translation, so the impact of pre-processing storage condition on EV isolation is a barrier for utilization of this MSC manufacturing by-product. To address this problem, the effects of the pre-processing storage conditions on EV isolation, characterization, and function were assessed using a conditioned medium (CM) derived from human umbilical cord-derived MSCs (HUC-MSCs). Hypothesis: The comparison of three different pre-processing storage conditions of CM immediately processed for EV isolation would reveal differences in EVs, and thus, suggest an optimal pre-processing storage condition. The results showed that EVs derived from a CM stored at room temperature, 4 °C, −20 °C, and −80 °C for at least one week were not grossly different from EVs isolated from the CM immediately after collection. EVs derived from an in pre-processing −80 °C storage condition had a significantly reduced polydispersity index, and significantly enhanced dot blot staining, but their zeta potential, hydrodynamic size, morphology and size in transmission electron microscopy were not significantly different from EVs derived from the CM immediately processed for isolation. There was no impact of pre-processing storage condition on the proliferation of sarcoma cell lines exposed to EVs. These data suggest that the CM produced during GMP-manufacturing of MSCs for clinical applications might be stored at −80 °C prior to EV isolation, and this may enable production scale-up, and thus, and enable preclinical and clinical testing, and EV lot qualification.
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Affiliation(s)
- Adrienne Wright
- Department of Anatomy and Physiology, Kansas State University, Manhattan, KS 66506, USA; (A.W.); (O.L.S.); (H.H.)
| | - Orman L. Snyder
- Department of Anatomy and Physiology, Kansas State University, Manhattan, KS 66506, USA; (A.W.); (O.L.S.); (H.H.)
| | - Lane K. Christenson
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA;
| | - Hong He
- Department of Anatomy and Physiology, Kansas State University, Manhattan, KS 66506, USA; (A.W.); (O.L.S.); (H.H.)
| | - Mark L. Weiss
- Department of Anatomy and Physiology, Midwest Institute of Comparative Stem Cell Biotechnology, Kansas State University, Manhattan, KS 66506, USA
- Correspondence: ; Tel.: +1-785-532-4520
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44
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Chen P, Tang S, Gao H, Zhang H, Chen C, Fang Z, Peng G, Weng H, Chen A, Zhang C, Qiu Z, Li S, Chen J, Chen L, Chen X. Wharton's jelly mesenchymal stem cell-derived small extracellular vesicles as natural nanoparticles to attenuate cartilage injury via microRNA regulation. Int J Pharm 2022; 623:121952. [PMID: 35753534 DOI: 10.1016/j.ijpharm.2022.121952] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 06/15/2022] [Accepted: 06/20/2022] [Indexed: 10/17/2022]
Abstract
The main strategy of tissue repair and regeneration focuses on the application of mesenchymal stem cells and cell-based nanoparticles, but there are still multiple challenges that may have negative impacts on human safety and therapeutic efficacy. Cell-free nanotechnology can effectively overcome these obstacles and limitations. Mesenchymal stem cell (MSC)-derived natural small extracellular vesicles (sEVs) represent ideal nanotherapeutics due to their low immunogenicity and lack of tumorigenicity. Here, sEVs harvested from Wharton's jelly mesenchymal stem cells (WJMSCs) were identified. In vitro results showed that WJMSC-sEVs efficiently entered chondrocytes in the osteoarthritis (OA) model, further promoted chondrocyte migration and proliferation and modulated immune reactivity. In vivo, WJMSC-sEVs notably promoted chondrogenesis, which was consistent with the effect of WJMSCs. RNA sequencing results revealed that sEV-microRNA-regulated biocircuits can significantly contribute to the treatment of OA, such as by promoting the activation of the calcium signaling pathway, ECM-receptor interaction pathway and NOTCH signaling pathway. In particular, let-7e-5p, which is found in WJMSC-sEVs, was shown to be a potential core molecule for promoting cartilage regeneration by regulating the levels of STAT3 and IGF1R. Our findings suggest that WJMSC-sEV-induced chondrogenesis is a promising innovative and feasible cell-free nanotherapy for OA treatment.
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Affiliation(s)
- Penghong Chen
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, 350004, China
| | - Shijie Tang
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, 350004, China
| | - Hangqi Gao
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, 350004, China
| | - Haoruo Zhang
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, 350004, China
| | - Caixiang Chen
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, 350004, China
| | - Zhuoqun Fang
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, 350004, China
| | - Guohao Peng
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, 350004, China
| | - Haiyan Weng
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, 350004, China
| | - Aizhen Chen
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, 350004, China
| | - Chaoyu Zhang
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, 350004, China
| | - Zhihuang Qiu
- Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Cardiac Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Shirong Li
- Department of Plastic and Reconstructive Surgery, Shinrong Plastic Surgery Hospital, Chongqing, China
| | - Jinghua Chen
- Department of Pharmaceutical Analysis, the School of Pharmacy, Fujian Medical University, Fuzhou, 350100, China.
| | - Liangwan Chen
- Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China; Department of Cardiac Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
| | - Xiaosong Chen
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, 350001, China.
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45
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Piao L, Huang Z, Inoue A, Kuzuya M, Cheng XW. Human umbilical cord-derived mesenchymal stromal cells ameliorate aging-associated skeletal muscle atrophy and dysfunction by modulating apoptosis and mitochondrial damage in SAMP10 mice. Stem Cell Res Ther 2022; 13:226. [PMID: 35659361 PMCID: PMC9166592 DOI: 10.1186/s13287-022-02895-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 05/11/2022] [Indexed: 11/13/2022] Open
Abstract
Background Skeletal muscle mass and function losses in aging individuals are associated with quality of life deterioration and disability. Mesenchymal stromal cells exert immunomodulatory and anti-inflammatory effects and could yield beneficial effects in aging-related degenerative disease. Methods and results We investigated the efficacy of umbilical cord-derived mesenchymal stromal cells (UC-MSCs) on sarcopenia-related skeletal muscle atrophy and dysfunction in senescence-accelerated mouse prone 10 (SAMP10) mice. We randomly assigned 24-week-old male SAMP10 mice to a UC-MSC treatment group and control group. At 12 weeks post-injection, the UC-MSC treatment had ameliorated sarcopenia-related muscle changes in performance, morphological structures, and mitochondria biogenesis, and it enhanced the amounts of proteins or mRNAs for myosin heavy chain, phospho-AMP-activated protein kinase, phospho-mammalian target of rapamycin, phospho-extracellular signal-regulated kinase1/2, peroxisome proliferator-activated receptor-γ coactivator, GLUT-4, COX-IV, and hepatocyte growth factor in both gastrocnemius and soleus muscles, and it reduced the levels of proteins or mRNAs for cathepsin K, cleaved caspase-3/-8, tumor necrosis factor-α, monocyte chemoattractant protein-1, and gp91phox mRNAs. The UC-MSC treatment retarded mitochondria damage, cell apoptosis, and macrophage infiltrations, and it enhanced desmin/laminin expression and proliferating and CD34+/Integrin α7+ cells in both types of skeletal muscle of the SAMP10 mice. In vitro, we observed increased levels of HGF, PAX-7, and MoyD mRNAs at the 4th passage of UC-MSCs. Conclusions Our results suggest that UC-MSCs can improve sarcopenia-related skeletal muscle atrophy and dysfunction via anti-apoptosis, anti-inflammatory, and mitochondrial biogenesis mechanisms that might be mediated by an AMPK-PGC1-α axis, indicating that UC-MSCs may provide a promising treatment for sarcopenia/muscle diseases.
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Affiliation(s)
- Limei Piao
- Department of Human Life Cord Applied Cell Therapy, Graduate School of Medicine, Nagoya University, Nagoya, Aichi-ken, 466-8550, Japan.,Department of Cardiology and Hypertension, Yanbian University Hospital, Yanji, 133000, Jilin, People's Republic of China
| | - Zhe Huang
- Department of Human Life Cord Applied Cell Therapy, Graduate School of Medicine, Nagoya University, Nagoya, Aichi-ken, 466-8550, Japan.
| | - Aiko Inoue
- Department of Community Healthcare and Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Aichi-ken, 466-8550, Japan
| | - Masafumi Kuzuya
- Department of Community Healthcare and Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Aichi-ken, 466-8550, Japan.,Institute of Innovation for Future Society, Nagoya University Graduate School of Medicine, Nagoya, Aichi-ken, 466-8550, Japan
| | - Xian Wu Cheng
- Department of Human Life Cord Applied Cell Therapy, Graduate School of Medicine, Nagoya University, Nagoya, Aichi-ken, 466-8550, Japan. .,Department of Cardiology and Hypertension, Yanbian University Hospital, Yanji, 133000, Jilin, People's Republic of China.
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The Combined Use of Platelet-Rich Plasma Clot Releasate and Allogeneic Human Umbilical Cord Mesenchymal Stem Cells Rescue Glucocorticoid-Induced Osteonecrosis of the Femoral Head. Stem Cells Int 2022; 2022:7432665. [PMID: 35547633 PMCID: PMC9085365 DOI: 10.1155/2022/7432665] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 04/10/2022] [Accepted: 04/13/2022] [Indexed: 11/17/2022] Open
Abstract
Glucocorticoid-induced osteonecrosis of the femoral head (ONFH) is a refractory disease. The treatment options for ONFH, especially nonsurgical ones, merit further investigation. To evaluate the combinatorial therapeutic effects of platelet-rich plasma clot releasate (PRCR) and umbilical cord mesenchymal stem cells (UC-MSCs) on glucocorticoid-induced ONFH, a dexamethasone (DEX)-treated cell model and a high-dose methylprednisolone (MPS)-treated rat model were established. Cell counting kit-8 (CCK-8) assay was performed in vitro to determine the optimum dosage of PRCR for UC-MSC viability. The effects of PRCR, UC-MSCs, and PRCR + UC-MSCs on cell viability, apoptosis, migration, and differentiation capacities of DEX-treated bone marrow mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cell (HUVECs) were explored via Transwell assays. Western blotting was conducted to evaluate the expression levels of RUNX2, VEGF, caspase-3, and Bcl-2 in the coculture systems. Ultrasound-guided intra-articular PRCR, UC-MSCs, and PRCR + UC-MSC injections were performed on the ONFH model rats. Microcomputed tomography, histological and immunohistochemical analyses, tartrate-resistant acid phosphatase (TRAP) staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to assess the therapeutic effects of PRCR and UC-MSCs on bone loss and necrosis induced by high-dose MPS. Results of this study revealed that the in vitro application of PRCR, UC-MSCs, and PRCR + UC-MSCs reversed the impaired proliferation and migration capacities and resisted apoptosis of BMSCs and HUVECs induced by DEX. Moreover, the PRCR and UC-MSC application significantly improved the alkaline phosphatase (ALP) and alizarin red (ALR) staining of BMSCs and tube formation capacity of HUVECs and promoted the protein expression of RUNX2 in BMSCs and VEGF in HUVECs. Similarly, in the ONFH rat model, the intra-articular injection of UC-MSCs and PRCR improved the subchondral bone mass parameters; promoted the expression of ALP, RUNX2, and VEGF; suppressed osteoclast overactivity; and resisted cell apoptosis. The combination of PRCR and UC-MSCs shows promising therapeutic effects in treating glucocorticoid-induced ONFH. The current study provides important information on intra-articular therapy, paving the way for the clinical management of ONFH in the future.
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Cao Q, Huang C, Chen XM, Pollock CA. Mesenchymal Stem Cell-Derived Exosomes: Toward Cell-Free Therapeutic Strategies in Chronic Kidney Disease. Front Med (Lausanne) 2022; 9:816656. [PMID: 35386912 PMCID: PMC8977463 DOI: 10.3389/fmed.2022.816656] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 02/24/2022] [Indexed: 12/12/2022] Open
Abstract
Chronic kidney disease (CKD) is rising in global prevalence and has become a worldwide public health problem, with adverse outcomes of kidney failure, cardiovascular disease, and premature death. However, current treatments are limited to slowing rather than reversing disease progression or restoring functional nephrons. Hence, innovative strategies aimed at kidney tissue recovery hold promise for CKD therapy. Mesenchymal stem cells (MSCs) are commonly used for regenerative therapy due to their potential for proliferation, differentiation, and immunomodulation. Accumulating evidence suggests that the therapeutic effects of MSCs are largely mediated by paracrine secretion of extracellular vesicles (EVs), predominantly exosomes. MSC-derived exosomes (MSC-Exos) replicate the functions of their originator MSCs via delivery of various genetic and protein cargos to target cells. More recently, MSC-Exos have also been utilized as natural carriers for targeted drug delivery. Therapeutics can be effectively incorporated into exosomes and then delivered to diseased tissue. Thus, MSC-Exos have emerged as a promising cell-free therapy in CKD. In this paper, we describe the characteristics of MSC-Exos and summarize their therapeutic efficacy in preclinical animal models of CKD. We also discuss the potential challenges and strategies in the use of MSC-Exos-based therapies for CKD in the future.
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Affiliation(s)
- Qinghua Cao
- Renal Medicine, Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Chunling Huang
- Renal Medicine, Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Xin-Ming Chen
- Renal Medicine, Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Carol A Pollock
- Renal Medicine, Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, Royal North Shore Hospital, St Leonards, NSW, Australia
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Gonzalez-Vilchis RA, Piedra-Ramirez A, Patiño-Morales CC, Sanchez-Gomez C, Beltran-Vargas NE. Sources, Characteristics, and Therapeutic Applications of Mesenchymal Cells in Tissue Engineering. Tissue Eng Regen Med 2022; 19:325-361. [PMID: 35092596 PMCID: PMC8971271 DOI: 10.1007/s13770-021-00417-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/24/2021] [Accepted: 12/05/2021] [Indexed: 01/31/2023] Open
Abstract
Tissue engineering (TE) is a therapeutic option within regenerative medicine that allows to mimic the original cell environment and functional organization of the cell types necessary for the recovery or regeneration of damaged tissue using cell sources, scaffolds, and bioreactors. Among the cell sources, the utilization of mesenchymal cells (MSCs) has gained great interest because these multipotent cells are capable of differentiating into diverse tissues, in addition to their self-renewal capacity to maintain their cell population, thus representing a therapeutic alternative for those diseases that can only be controlled with palliative treatments. This review aimed to summarize the state of the art of the main sources of MSCs as well as particular characteristics of each subtype and applications of MSCs in TE in seven different areas (neural, osseous, epithelial, cartilage, osteochondral, muscle, and cardiac) with a systemic revision of advances made in the last 10 years. It was observed that bone marrow-derived MSCs are the principal type of MSCs used in TE, and the most commonly employed techniques for MSCs characterization are immunodetection techniques. Moreover, the utilization of natural biomaterials is higher (41.96%) than that of synthetic biomaterials (18.75%) for the construction of the scaffolds in which cells are seeded. Further, this review shows alternatives of MSCs derived from other tissues and diverse strategies that can improve this area of regenerative medicine.
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Affiliation(s)
- Rosa Angelica Gonzalez-Vilchis
- Molecular Biology Undergraduate Program, Natural Science and Engineering Division, Cuajimalpa Unit, Autonomous Metropolitan University, 05340, CDMX, Mexico
| | - Angelica Piedra-Ramirez
- Molecular Biology Undergraduate Program, Natural Science and Engineering Division, Cuajimalpa Unit, Autonomous Metropolitan University, 05340, CDMX, Mexico
| | - Carlos Cesar Patiño-Morales
- Research Laboratory of Developmental Biology and Experimental Teratogenesis, Children's Hospital of Mexico Federico Gomez, 06720, CDMX, Mexico
| | - Concepcion Sanchez-Gomez
- Research Laboratory of Developmental Biology and Experimental Teratogenesis, Children's Hospital of Mexico Federico Gomez, 06720, CDMX, Mexico
| | - Nohra E Beltran-Vargas
- Department of Processes and Technology, Natural Science and Engineering Division, Cuajimalpa Unit, Autonomous Metropolitan University, Cuajimalpa. Vasco de Quiroga 4871. Cuajimalpa de Morelos, 05348, CDMX, Mexico.
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Fathi-Karkan S, Banimohamad-Shotorbani B, Saghati S, Rahbarghazi R, Davaran S. A critical review of fibrous polyurethane-based vascular tissue engineering scaffolds. J Biol Eng 2022; 16:6. [PMID: 35331305 PMCID: PMC8951709 DOI: 10.1186/s13036-022-00286-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 03/08/2022] [Indexed: 12/20/2022] Open
Abstract
Certain polymeric materials such as polyurethanes (PUs) are the most prevalent class of used biomaterials in regenerative medicine and have been widely explored as vascular substitutes in several animal models. It is thought that PU-based biomaterials possess suitable hemo-compatibility with comparable performance related to the normal blood vessels. Despite these advantages, the possibility of thrombus formation and restenosis limits their application as artificial functional vessels. In this regard, various surface modification approaches have been developed to enhance both hemo-compatibility and prolong patency. While critically reviewing the recent advances in vascular tissue engineering, mainly PU grafts, this paper summarizes the application of preferred cell sources to vascular regeneration, physicochemical properties, and some possible degradation mechanisms of PU to provide a more extensive perspective for future research.
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Affiliation(s)
- Sonia Fathi-Karkan
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Medical Nanotechnology, Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Golgasht St, Tabriz, Iran.,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behnaz Banimohamad-Shotorbani
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sepideh Saghati
- Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran. .,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Soodabeh Davaran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
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Regeneration of Chronic Rotator Cuff Tear in a Rabbit Model: Synergetic Benefits of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells, Polydeoxyribonucleotides, and Microcurrent Therapy. BIOMED RESEARCH INTERNATIONAL 2022; 2022:6496773. [PMID: 35342750 PMCID: PMC8941538 DOI: 10.1155/2022/6496773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 02/06/2022] [Accepted: 02/24/2022] [Indexed: 11/22/2022]
Abstract
Objective To investigate synergic therapeutic effects of combined injection of intralesional mesenchymal stem cells derived from human umbilical cord blood (UCB-MSCs) and polydeoxyribonucleotide (PDRN) combined with microcurrent therapy (MIC) on full thickness rotator cuff tendon tear (FTRCTT) in rabbit models. Methods Thirty-two rabbit models were assigned to 4 different groups. FTRCTT in the supraspinatus tendon was created. After 6 weeks, 4 types of procedures (0.2 mL normal saline injection, group 1 (G1-NS); 0.2 mL SC injection, group 2 (G2-MSC); 0.2 mL SC and weekly four injections of 0.2 mL PDRN with sham MIC, group 3 (G3-MSC+PDRN+sham MIC); and 0.2 mL SC and weekly four injections of 0.2 mL PDRN with MIC for four weeks, group 4 (G4-MSC+PDRN+MIC)) were performed in FTRCTT. Gross morphologic and histological changes of proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF) and platelet endothelial cell adhesion molecule (PECAM-1) and motion analysis were performed. Results There was a significant difference in gross morphologic changes between baseline and week 4 posttreatment in group 4 compared to the other three groups (p = 0.01). In groups 3 and 4, all parameters of histochemical and motion analysis have been found to be significantly greater than the ones in groups 1 and 2 (p < 0.05). In group 4, PCNA-, VEGF-, and PECAM-1-stained cells, as well as walking distance, were significantly greater than the ones in group 3 (p < 0.05). Conclusion The treatment with UCB-MSCs and PDRN combined with MIC might be the most effective in rabbit models' traumatic FRTCTT.
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