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Li R, Wang H, Wang X, Yang Y, Zhong K, Zhang X, Li H. MSC-EVs and UCB-EVs promote skin wound healing and spatial transcriptome analysis. Sci Rep 2025; 15:4006. [PMID: 39893214 PMCID: PMC11787299 DOI: 10.1038/s41598-025-87592-6] [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: 11/13/2024] [Accepted: 01/20/2025] [Indexed: 02/04/2025] Open
Abstract
Extracellular vesicles (EVs) are important paracrine mediators derived from various cells and biological fluids, including plasma, that are capable of inducing regenerative effects by transferring bioactive molecules such as microRNAs (miRNAs). This study investigated the effect of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) isolated from umbilical cord blood and human umbilical cord plasma-derived extracellular vesicles (UCB-EVs) on wound healing and scar formation reduction. Spatial transcriptomics (ST) was used to study the effects of MSC-EVs and UCB-EVs on the heterogeneity of major cell types and wound healing pathways in mouse skin tissue. MSC-EVs and UCB-EVs were isolated using ultracentrifugation and identified using transmission electron microscopy, nanoparticle tracking analysis, and western blot. The effects of MSC-EVs and UCB-EVs on human dermal fibroblast-adult cell (HDF-a) migration and proliferation were evaluated using cell scratch assays, cell migration assays, and cell proliferation assays. In vivo, MSC-EVs and UCB-EVs were injected around full-cut wounds to evaluate their efficacy of wound healing by measuring wound closure rates and scar width and performing histological analysis. ST was performed on skin tissue samples from mice in each group after wound healing to analyze the heterogeneity of major cell types compared with the control group and investigate potential mechanisms affecting wound healing and scar formation. In vitro experiments demonstrated that MSC-EVs and UCB-EVs promoted the proliferation and migration of HDF-a cells. Local injection of MSC-EVs and UCB-EVs into the periphery of a mouse skin wound accelerated re-epithelialization, promoted wound healing, and reduced scar width. ST analysis of skin tissue from each group after wound healing revealed that MSC-EVs and UCB-EVs reduced the relative expression of marker genes in myofibroblasts, regulated wound healing, and decreased scar formation by reducing the expression of the TGF-β signaling pathway and increasing the expression of the Wnt signaling pathway. The results suggest that MSC-EVs and UCB-EVs play a significant role in the activity of cord blood plasma-derived mesenchymal stem cells and cord blood plasma. They can be considered promising new agents for promoting skin wound healing.
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Affiliation(s)
- Ruonan Li
- Key Laboratory of Animal Biochemistry and Nutrition of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, No.15 Longzihu University Area, Zhengdong New District, Zhengzhou, 450046, China
| | - Haotian Wang
- Key Laboratory of Animal Biochemistry and Nutrition of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, No.15 Longzihu University Area, Zhengdong New District, Zhengzhou, 450046, China
| | - Xiaolong Wang
- HenanYinfeng Biological Engineering Technology Co., LTD, No. 11 Changchun Road, Zhengzhou High tech Industrial Development Zone, Zhengzhou, 450000, China
| | - Yanbin Yang
- Key Laboratory of Animal Biochemistry and Nutrition of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, No.15 Longzihu University Area, Zhengdong New District, Zhengzhou, 450046, China
| | - Kai Zhong
- Key Laboratory of Animal Biochemistry and Nutrition of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, No.15 Longzihu University Area, Zhengdong New District, Zhengzhou, 450046, China.
| | - Xuemei Zhang
- HenanYinfeng Biological Engineering Technology Co., LTD, No. 11 Changchun Road, Zhengzhou High tech Industrial Development Zone, Zhengzhou, 450000, China.
| | - Heping Li
- Key Laboratory of Animal Biochemistry and Nutrition of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, No.15 Longzihu University Area, Zhengdong New District, Zhengzhou, 450046, China.
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Ojeh N, Vecin NM, Pastar I, Volk SW, Wilgus T, Griffiths S, Ramey‐Ward AN, Driver VR, DiPietro LA, Gould LJ, Tomic‐Canic M. The Wound Reporting in Animal and Human Preclinical Studies (WRAHPS) Guidelines. Wound Repair Regen 2025; 33:e13232. [PMID: 39639458 PMCID: PMC11621255 DOI: 10.1111/wrr.13232] [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: 07/19/2024] [Revised: 10/02/2024] [Accepted: 10/28/2024] [Indexed: 12/07/2024]
Abstract
Preclinical studies for wound healing disorders are an essential step in translating discoveries into therapies. Also, they are an integral component of initial safety screening and gaining mechanistic insights using an in vivo approach. Given the complexity of the wound healing process, existing guidelines for animal testing do not capture key information due to the inevitable variability in experimental design. Variations in study interpretation are increased by complexities associated with wound aetiology, wounding procedure, multiple treatment conditions, wound assessment, and analysis, as well as lack of acknowledgement of limitation of the model used. Yet, no standards exist to guide reporting crucial experimental information required to interpret results in translational studies of wound healing. Consistency in reporting allows transparency, comparative, and meta-analysis studies and avoids repetition and redundancy. Therefore, there is a critical and unmet need to standardise reporting for preclinical wound studies. To aid in reporting experimental conditions, The Wound Reporting in Animal and Human Preclinical Studies (WRAHPS) Guidelines have now been created by the authors working with the Wound Care Collaborative Community (WCCC) GAPS group to provide a checklist and reporting template for the most frequently used preclinical models in support of development for human clinical trials for wound healing disorders. It is anticipated that the WRAHPS Guidelines will standardise comprehensive methods for reporting in scientific manuscripts and the wound healing field overall. This article is not intended to address regulatory requirements but is intended to provide general guidelines on important scientific considerations for such studies.
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Affiliation(s)
- Nkemcho Ojeh
- Wound Healing and Regenerative Medicine Research Program, Dr Phillip Frost Department of Dermatology and Cutaneous SurgeryUniversity of Miami Miller School of MedicineMiamiFloridaUSA
- Department of Preclinical and Health Sciences, Faculty of Medical SciencesThe University of the West IndiesBridgetownBarbados
| | - Nicole M. Vecin
- Wound Healing and Regenerative Medicine Research Program, Dr Phillip Frost Department of Dermatology and Cutaneous SurgeryUniversity of Miami Miller School of MedicineMiamiFloridaUSA
| | - Irena Pastar
- Wound Healing and Regenerative Medicine Research Program, Dr Phillip Frost Department of Dermatology and Cutaneous SurgeryUniversity of Miami Miller School of MedicineMiamiFloridaUSA
| | - Susan W. Volk
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Traci Wilgus
- Department of PathologyThe Ohio State UniversityColumbusOhioUSA
| | | | | | - Vickie R. Driver
- School of MedicineWashington State UniversitySpokaneWashingtonUSA
| | - Luisa A. DiPietro
- Center for Wound Healing and Tissue RegenerationUniversity of Illinois ChicagoChicagoIllinoisUSA
| | - Lisa J. Gould
- South Shore Hospital Center for Wound HealingWeymouthMassachusettsUSA
| | - Marjana Tomic‐Canic
- Wound Healing and Regenerative Medicine Research Program, Dr Phillip Frost Department of Dermatology and Cutaneous SurgeryUniversity of Miami Miller School of MedicineMiamiFloridaUSA
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Wu S, Zhou Z, Li Y, Jiang J. Advancements in diabetic foot ulcer research: Focus on mesenchymal stem cells and their exosomes. Heliyon 2024; 10:e37031. [PMID: 39286219 PMCID: PMC11403009 DOI: 10.1016/j.heliyon.2024.e37031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/11/2024] [Accepted: 08/26/2024] [Indexed: 09/19/2024] Open
Abstract
Diabetes represents a widely acknowledged global public health concern. Diabetic foot ulcer (DFU) stands as one of the most severe complications of diabetes, its occurrence imposing a substantial economic burden on patients, profoundly impacting their quality of life. Despite the deepening comprehension regarding the pathophysiology and cellular as well as molecular responses of DFU, the current therapeutic arsenal falls short of efficacy, failing to offer a comprehensive remedy for deep-seated chronic wounds and microvascular occlusions. Conventional treatments merely afford symptomatic alleviation or retard the disease's advancement, devoid of the capacity to effectuate further restitution of compromised vasculature and nerves. An escalating body of research underscores the prominence of mesenchymal stem cells (MSCs) owing to their paracrine attributes and anti-inflammatory prowess, rendering them a focal point in the realm of chronic wound healing. Presently, MSCs have been validated as a highly promising cellular therapeutic approach for DFU, capable of effectuating cellular repair, epithelialization, granulation tissue formation, and neovascularization by means of targeted differentiation, angiogenesis promotion, immunomodulation, and paracrine activities, thereby fostering wound healing. The secretome of MSCs comprises cytokines, growth factors, chemokines, alongside exosomes harboring mRNA, proteins, and microRNAs, possessing immunomodulatory and regenerative properties. The present study provides a systematic exposition on the etiology of DFU and elucidates the intricate molecular mechanisms and diverse functionalities of MSCs in the context of DFU treatment, thereby furnishing pioneering perspectives aimed at harnessing the therapeutic potential of MSCs for DFU management and advancing wound healing processes.
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Affiliation(s)
- ShuHui Wu
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - ZhongSheng Zhou
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yang Li
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jinlan Jiang
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
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Low Wang CC, Chong T, Moore G, Echalier B, Haakonsen N, Carter JE, Mathes D, Hsia J, Phan TT, Lim IJ, Freed BM. Results of the Phase 1 Open-Label Safety Study of Umbilical Cord Lining Mesenchymal Stromal/Stem Cells (Corlicyte ®) to Heal Chronic Diabetic Foot Ulcers. Biomedicines 2024; 12:1375. [PMID: 38927582 PMCID: PMC11201444 DOI: 10.3390/biomedicines12061375] [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: 04/23/2024] [Revised: 06/04/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND Mesenchymal stromal/stem cells (MSCs) play a critical role in wound healing. Corlicyte® is an MSC product derived from allogeneic umbilical cord tissue donated under an institutional review board-approved protocol and processed in accordance with section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act. This open-label phase 1 trial was performed under a United States Food and Drug Administration Investigational New Drug Application to establish the safety and tolerability of Corlicyte® in patients with diabetes and chronic diabetic foot ulcer (DFU). METHODS Escalating doses were applied topically twice a week for up to 8 weeks after ulcer debridement, wound photography, and measurement. Subjects were followed for 4 weeks after the treatment phase. Adverse events were assessed at every visit. RESULTS Nine subjects in 2 dosing cohorts completed the trial. No subjects experienced a serious adverse reaction to Corlicyte® or the development of anti-human leukocyte antigen (HLA) antibodies. Sixty percentage of subjects in the lower dose cohort experienced ulcer closure by Day 70 of follow-up, while the mean ulcer size was reduced by 54-67% in the other subjects. CONCLUSIONS Topical administration of Corlicyte®, a novel biologic therapy consisting of allogeneic umbilical cord lining MSCs, appeared safe and tolerable and resulted in a significant decrease in ulcer area, demonstrating its potential as a therapy for healing of chronic DFU.
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Affiliation(s)
- Cecilia C. Low Wang
- Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Tae Chong
- Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Garrett Moore
- Department of Orthopedics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;
| | - Benjamin Echalier
- University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Nicola Haakonsen
- University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - James E. Carter
- Department of Cardiovascular Medicine, Miller Family Heart, Vascular, and Thoracic Institute, Cleveland Clinic, Cleveland, OH 44195, USA;
| | - David Mathes
- Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;
| | - Judith Hsia
- Division of Cardiology, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;
- CPC Clinical Research, Aurora, CO 80045, USA
| | - Toan Thang Phan
- Cell Research Corporation Pte Ltd., Singapore 048943, Singapore; (T.T.P.); (I.J.L.)
| | - Ivor J. Lim
- Cell Research Corporation Pte Ltd., Singapore 048943, Singapore; (T.T.P.); (I.J.L.)
| | - Brian M. Freed
- Division of Allergy and Clinical Immunology, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;
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Hetta HF, Elsaghir A, Sijercic VC, Akhtar MS, Gad SA, Moses A, Zeleke MS, Alanazi FE, Ahmed AK, Ramadan YN. Mesenchymal stem cell therapy in diabetic foot ulcer: An updated comprehensive review. Health Sci Rep 2024; 7:e2036. [PMID: 38650719 PMCID: PMC11033295 DOI: 10.1002/hsr2.2036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 02/06/2024] [Accepted: 03/19/2024] [Indexed: 04/25/2024] Open
Abstract
Background Diabetes has evolved into a worldwide public health issue. One of the most serious complications of diabetes is diabetic foot ulcer (DFU), which frequently creates a significant financial strain on patients and lowers their quality of life. Up until now, there has been no curative therapy for DFU, only symptomatic relief or an interruption in the disease's progression. Recent studies have focused attention on mesenchymal stem cells (MSCs), which provide innovative and potential treatment candidates for several illnesses as they can differentiate into various cell types. They are mostly extracted from the placenta, adipose tissue, umbilical cord (UC), and bone marrow (BM). Regardless of their origin, they show comparable features and small deviations. Our goal is to investigate MSCs' therapeutic effects, application obstacles, and patient benefit strategies for DFU therapy. Methodology A comprehensive search was conducted using specific keywords relating to DFU, MSCs, and connected topics in the databases of Medline, Scopus, Web of Science, and PubMed. The main focus of the selection criteria was on English-language literature that explored the relationship between DFU, MSCs, and related factors. Results and Discussion Numerous studies are being conducted and have demonstrated that MSCs can induce re-epithelialization and angiogenesis, decrease inflammation, contribute to immunological modulation, and subsequently promote DFU healing, making them a promising approach to treating DFU. This review article provides a general snapshot of DFU (including clinical presentation, risk factors and etiopathogenesis, and conventional treatment) and discusses the clinical progress of MSCs in the management of DFU, taking into consideration the side effects and challenges during the application of MSCs and how to overcome these challenges to achieve maximum benefits. Conclusion The incorporation of MSCs in the management of DFU highlights their potential as a feasible therapeutic strategy. Establishing a comprehensive understanding of the complex relationship between DFU pathophysiology, MSC therapies, and related obstacles is essential for optimizing therapy outcomes and maximizing patient benefits.
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Affiliation(s)
- Helal F. Hetta
- Division of Microbiology, Immunology and Biotechnology, Department of Natural Products and Alternative MedicineFaculty of Pharmacy, University of TabukTabukSaudi Arabia
- Department of Medical Microbiology and ImmunologyFaculty of Medicine, Assiut UniversityAssiutEgypt
| | - Alaa Elsaghir
- Department of Microbiology and ImmunologyFaculty of Pharmacy, Assiut UniversityAssiutEgypt
| | | | | | - Sayed A. Gad
- Faculty of Medicine, Assiut UniversityAssiutEgypt
| | | | - Mahlet S. Zeleke
- Menelik II Medical and Health Science College, Kotebe Metropolitan UniversityAddis AbabaEthiopia
| | - Fawaz E. Alanazi
- Department of Pharmacology and ToxicologyFaculty of Pharmacy, University of TabukTabukSaudi Arabia
| | | | - Yasmin N. Ramadan
- Department of Microbiology and ImmunologyFaculty of Pharmacy, Assiut UniversityAssiutEgypt
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Panda D, Nayak S. Stem Cell-Based Tissue Engineering Approaches for Diabetic Foot Ulcer: a Review from Mechanism to Clinical Trial. Stem Cell Rev Rep 2024; 20:88-123. [PMID: 37867186 DOI: 10.1007/s12015-023-10640-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/05/2023] [Indexed: 10/24/2023]
Abstract
Diabetic foot ulcer (DFU) is a complication from incomplete or prolonged wound healing, at times requires amputation, putting substantial health and socioeconomic burden. Wound healing is a dynamic overlapping process that can be regulated by arrays of molecular factors showing redundancy in function. However, dysregulation in the mechanism of angiogenesis, extra cellular matrix (ECM) formation and immune modulation are the major causes for impair wound healing in hyperglycaemic patients. Despite development of wound care research, there is a lack of well-accepted targeted therapy with multidisciplinary approach for DFU treatment. Stem cell therapy holds a promising outcome both in preclinical and clinical trials because of its ability to promote healing via regeneration and specialized tissue differentiation. Among different types of stem cells, regenerative potential of mesenchymal stem cell (MSC) is well demonstrated in both experimental and clinical trial. Still there is a huge knowledge gap among medical practitioners for deciding the best stem cell source, administration route, and safety. This review strengthens the fact that why stem cell therapy is a promising candidate to treat DFU and cited multiple tissue engineering and biomaterial-based approaches for delivering stem cells and their aftermath paracrine events. Based on the pre-clinical and clinical studies, the review tried to come up with optimum stem cell source and delivery route for the treatment of DFU. At last, the review glances on possible direction to enhance therapeutics strategy for the same, including different approaches like: phytocompounds, exosomes, scaffold geometry, cell preconditioning and licensing etc.
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Affiliation(s)
- Debarchan Panda
- Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Sunita Nayak
- Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.
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Asadi R, Mostafavinia A, Amini A, Ahmadi H, Ahrabi B, Omidi H, Pourhashemi E, Hajihosseintehrani M, Rezaei F, Mohsenifar Z, Chien S, Bayat M. Acceleration of a delayed healing wound repair model in diabetic rats by additive impacts of photobiomodulation plus conditioned medium of adipose-derived stem cells. J Diabetes Metab Disord 2023; 22:1551-1560. [PMID: 37975122 PMCID: PMC10638220 DOI: 10.1007/s40200-023-01285-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 08/17/2023] [Indexed: 11/19/2023]
Abstract
PURPOSE This study aimed to investigate the effects of photobiomodulation (PBM) and conditioned medium (CM) derived from human adipose-derived stem cells (h-ASCs), both individually and in combination, on the maturation stage of an ischemic infected delayed healing wound model (IIDHWM) in type I diabetic (TIDM) rats. METHODS The study involved the extraction of h-ASCs from donated fat, assessment of their immunophenotypic markers, cell culture, and extraction and concentration of CM from cultured 1 × 10^6 h-ASCs. TIDM was induced in 24 male adult rats, divided into four groups: control, CM group, PBM group (80 Hz, 0.2 J/cm2, 890 nm), and rats receiving both CM and PBM. Clinical and laboratory evaluations were conducted on days 4, 8, and 16, and euthanasia was performed using CO2 on day 16. Tensiometrical and stereological examinations were carried out using two wound samples from each rat. RESULTS Across all evaluated factors, including wound closure ratio, microbiological, tensiometrical, and stereological parameters, similar patterns were observed. The outcomes of CM + PBM, PBM, and CM treatments were significantly superior in all evaluated parameters compared to the control group (p = 0.000 for all). Both PBM and CM + PBM treatments showed better tensiometrical and stereological results than CM alone (almost all, p = 0.000), and CM + PBM outperformed PBM alone in almost all aspects (p = 0.000). Microbiologically, both CM + PBM and PBM exhibited fewer colony-forming units (CFU) than CM alone (both, p = 0.000). CONCLUSION PBM, CM, and CM + PBM interventions substantially enhanced the maturation stage of the wound healing process in IIDHWM of TIDM rats by mitigating the inflammatory response and reducing CFU count. Moreover, these treatments promoted new tissue formation in the wound bed and improved wound strength. Notably, the combined effects of CM + PBM surpassed the individual effects of CM and PBM. SUPPLEMENTARY INFORMATION The online version contains supplementary material available at 10.1007/s40200-023-01285-3.
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Affiliation(s)
- Robabeh Asadi
- Department of Paramedicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Atarodalsadat Mostafavinia
- Department of Anatomical Sciences and Cognitive Neuroscience, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Abdollah Amini
- Department of Biology and Anatomical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Houssein Ahmadi
- Department of Biology and Anatomical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behnaz Ahrabi
- Department of Biology and Anatomical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamidreza Omidi
- Department of Biology and Anatomical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | | | | | - Zhaleh Mohsenifar
- Department of Pathology, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sufan Chien
- Price Institute of Surgical Research, University of Louisville, and Noveratech LLC of Louisville, Louisville, USA
| | - Mohammad Bayat
- Price Institute of Surgical Research, University of Louisville, and Noveratech LLC of Louisville, Louisville, USA
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Yadav JP. Based on Clinical Research Matrix Metalloprotease (MMP) Inhibitors to Promote Diabetic Wound Healing. Horm Metab Res 2023; 55:752-757. [PMID: 37798905 DOI: 10.1055/a-2171-5879] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/07/2023]
Abstract
Chronic inflammation is a common factor in obesity, diabetes mellitus, and the complications of diabetes, including diabetic wounds. These ulcers are characterized by persistent lesions that are challenging to heal, significantly decreasing patients' quality of life and imposing a substantial financial burden on society. MMP are zinc endopeptidases that play a role in wound healing in response to various stimuli, including diabetes mellitus. MMP levels fluctuate throughout the wound healing process in diabetic patients' serum, skin tissues, and wound fluid, indicating their potential as biomarkers for diabetic foot ulcers. Targeting MMP has emerged as a promising strategy for treating diabetic wounds, as these enzymes are involved in critical biological processes related to wound healing, including extracellular matrix secretion, angiogenesis, granulation tissue formation, collagen growth, re-epithelization, inflammatory response, and oxidative stress.
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Affiliation(s)
- Jagat Pal Yadav
- Faculty of Pharmaceutical Sciences, Rama University, Kanpur, India
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Panthi VK, Imran M, Chaudhary A, Paudel KR, Mohammed Y. The significance of quercetin-loaded advanced nanoformulations for the management of diabetic wounds. Nanomedicine (Lond) 2023; 18:391-411. [PMID: 37140389 DOI: 10.2217/nnm-2022-0281] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/05/2023] Open
Abstract
Quercetin is a well-known plant flavanol that exhibits multiple biological activities, including antioxidant, anti-inflammatory and anticancer activities. The role of quercetin in wound healing has been widely explored by a range of researchers in different models. However, the physicochemical properties, such as solubility and permeability, of this compound are low, which ultimately limits its bioavailability on the target site. To overcome these limitations for successful therapy, scientists have developed a range of nanoformulations that provide effective therapeutic potential. In this review, the broad mechanism of quercetin for acute and chronic wounds is covered. A compilation of recent advances on the horizon of wound healing via quercetin is incorporated with several advanced nanoformulations.
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Affiliation(s)
- Vijay Kumar Panthi
- Department of Pharmacy, College of Pharmacy & Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam, 58554, Republic of Korea
| | - Mohammad Imran
- Therapeutic Research Group, Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, 4102, Australia
| | - Arshi Chaudhary
- Department of Pharmaceutics, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India
| | - Keshav Raj Paudel
- Department of Oriental Medicine Resources, Mokpo National University, Muan-gun, Jeonnam, 58554, Republic of Korea
| | - Yousuf Mohammed
- Therapeutic Research Group, Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, 4102, Australia
- School of Pharmacy, The University of Queensland, Brisbane, 4102, Australia
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10
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Yu X, Liu P, Li Z, Zhang Z. Function and mechanism of mesenchymal stem cells in the healing of diabetic foot wounds. Front Endocrinol (Lausanne) 2023; 14:1099310. [PMID: 37008908 PMCID: PMC10061144 DOI: 10.3389/fendo.2023.1099310] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
Diabetes has become a global public health problem. Diabetic foot is one of the most severe complications of diabetes, which often places a heavy economic burden on patients and seriously affects their quality of life. The current conventional treatment for the diabetic foot can only relieve the symptoms or delay the progression of the disease but cannot repair damaged blood vessels and nerves. An increasing number of studies have shown that mesenchymal stem cells (MSCs) can promote angiogenesis and re-epithelialization, participate in immune regulation, reduce inflammation, and finally repair diabetic foot ulcer (DFU), rendering it an effective means of treating diabetic foot disease. Currently, stem cells used in the treatment of diabetic foot are divided into two categories: autologous and allogeneic. They are mainly derived from the bone marrow, umbilical cord, adipose tissue, and placenta. MSCs from different sources have similar characteristics and subtle differences. Mastering their features to better select and use MSCs is the premise of improving the therapeutic effect of DFU. This article reviews the types and characteristics of MSCs and their molecular mechanisms and functions in treating DFU to provide innovative ideas for using MSCs to treat diabetic foot and promote wound healing.
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Affiliation(s)
- Xiaoping Yu
- School of Medicine and Nursing, Chengdu University, Chengdu, Sichuan, China
| | - Pan Liu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Zheng Li
- People’s Hospital of Jiulongpo District, Chongqing, China
| | - Zhengdong Zhang
- School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Orthopedics, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
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Chiu A, Sharma D, Zhao F. Tissue Engineering-Based Strategies for Diabetic Foot Ulcer Management. Adv Wound Care (New Rochelle) 2023; 12:145-167. [PMID: 34939837 PMCID: PMC9810358 DOI: 10.1089/wound.2021.0081] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 10/26/2021] [Indexed: 01/13/2023] Open
Abstract
Significance: Diabetic foot ulcers (DFU) are a mounting problem with the increasingly frail population. Injuries that would otherwise heal are kept open by risk factors such as diabetes, obesity, and age-related conditions, which interferes with the natural wound healing processes. Recent Advances: This review summarizes recent advancements in the field of tissue engineering for the treatment of DFUs. FDA-approved approaches, including signaling-based therapies, stem cell therapies, and skin substitutes are summarized and cutting-edge experimental technologies that have the potential to manage chronic wounds, such as skin printing, skin organogenesis, skin self-assembly, and prevascularization, are discussed. Critical Issues: The standard of care for chronic wounds involves wound debridement, wound dressings, and resolving the underlying cause such as lowering the glycemic index and reducing wound pressure. Current DFU treatments are limited by low wound closure rates and poor regrown skin quality. New adjuvant therapies that facilitate wound closure in place of or in conjunction with standard care are critically needed. Future Directions: Tissue engineering strategies are limited by the plasticity of adult human cells. In addition to traditional techniques, genetic modification, although currently an emerging technology, has the potential to unlock human regeneration and can be incorporated in future therapeutics.
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Affiliation(s)
- Alvis Chiu
- Department of Biomedical Engineering, Texas A&M University, College Station, Texas, USA
| | - Dhavan Sharma
- Department of Biomedical Engineering, Texas A&M University, College Station, Texas, USA
| | - Feng Zhao
- Department of Biomedical Engineering, Texas A&M University, College Station, Texas, USA
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12
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Sun Y, Xu H, Tan B, Yi Q, Liu H, Tian J, Zhu J. Andrographolide-treated bone marrow mesenchymal stem cells-derived conditioned medium protects cardiomyocytes from injury by metabolic remodeling. Mol Biol Rep 2023; 50:2651-2662. [PMID: 36641493 DOI: 10.1007/s11033-023-08250-6] [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: 06/02/2022] [Accepted: 01/04/2023] [Indexed: 01/15/2023]
Abstract
BACKGROUND Bone marrow mesenchymal stem cells (BMSCs) transplantation therapy providing a great hope for the recovery of myocardial ischemic hypoxic injury. However, the microenvironment after myocardial injury is not conducive to the survival of BMSCs, which limits the therapeutic application of BMSCs. Our previous study has confirmed that the survival of BMSCs cells in the glucose and serum deprivation under hypoxia (GSDH) is increased after Andrographolide (AG) pretreatment, but whether this treatment could improve the effect of BMSCs in repairing of myocardial injury has not been verified. METHODS AND RESULT We first treated H9C2 with GSDH to simulate the microenvironment of myocardial injury in vitro, then we pretreated rat primary BMSCs with AG, and collected conditioned medium derived from BMSCs (BMSCs-CM) and conditioned medium derived from AG-pretreated BMSCs (AG-BMSCs-CM) after GSDH treatment. And they were used to treat H9C2 cells under GSDH to further detect oxidative stress and metabolic changes. The results showed that AG-BMSCs-CM could be more advantageous for cardiomyocyte injury repair than BMSCs-CM, as indicated by the decrease of apoptosis rate and oxidative stress. The changes of mitochondria and lipid droplets results suggested that AG-BMSCs-CM can regulate metabolic remodeling of H9C2 cells to repair cell injury, and that AMPK was activated during this process. CONCLUSIONS This study demonstrates, for the first time, the protective effect of AG-BMSCs-CM on GSDH-induced myocardial cell injury, providing a potential therapeutic strategy for clinical application.
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Affiliation(s)
- Yanting Sun
- Department of Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, 136 Zhongshan Er Road, Chongqing, 400014, China.,Centre of Clinical Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Hao Xu
- Department of Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, 136 Zhongshan Er Road, Chongqing, 400014, China.,Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Bin Tan
- Department of Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, 136 Zhongshan Er Road, Chongqing, 400014, China
| | - Qin Yi
- Department of Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, 136 Zhongshan Er Road, Chongqing, 400014, China
| | - Huiwen Liu
- Department of Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, 136 Zhongshan Er Road, Chongqing, 400014, China
| | - Jie Tian
- Department of Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, 136 Zhongshan Er Road, Chongqing, 400014, China.,Department of Cardiovascular (Internal Medicine), Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Jing Zhu
- Department of Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, 136 Zhongshan Er Road, Chongqing, 400014, China.
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13
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Chen J, Qin S, Liu S, Zhong K, Jing Y, Wu X, Peng F, Li D, Peng C. Targeting matrix metalloproteases in diabetic wound healing. Front Immunol 2023; 14:1089001. [PMID: 36875064 PMCID: PMC9981633 DOI: 10.3389/fimmu.2023.1089001] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 02/06/2023] [Indexed: 02/19/2023] Open
Abstract
Chronic inflammation participates in the progression of multiple chronic diseases, including obesity, diabetes mellitus (DM), and DM related complications. Diabetic ulcer, characterized by chronic wounds that are recalcitrant to healing, is a serious complication of DM tremendously affecting the quality of life of patients and imposing a costly medical burden on society. Matrix metalloproteases (MMPs) are a family of zinc endopeptidases with the capacity of degrading all the components of the extracellular matrix, which play a pivotal part in healing process under various conditions including DM. During diabetic wound healing, the dynamic changes of MMPs in the serum, skin tissues, and wound fluid of patients are in connection with the degree of wound recovery, suggesting that MMPs can function as essential biomarkers for the diagnosis of diabetic ulcer. MMPs participate in various biological processes relevant to diabetic ulcer, such as ECM secretion, granulation tissue configuration, angiogenesis, collagen growth, re-epithelization, inflammatory response, as well as oxidative stress, thus, seeking and developing agents targeting MMPs has emerged as a potential way to treat diabetic ulcer. Natural products especially flavonoids, polysaccharides, alkaloids, polypeptides, and estrogens extracted from herbs, vegetables, as well as animals that have been extensively illustrated to treat diabetic ulcer through targeting MMPs-mediated signaling pathways, are discussed in this review and may contribute to the development of functional foods or drug candidates for diabetic ulcer therapy. This review highlights the regulation of MMPs in diabetic wound healing, and the potential therapeutic ability of natural products for diabetic wound healing by targeting MMPs.
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Affiliation(s)
- Junren Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Siqi Qin
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shengmeng Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Kexin Zhong
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yiqi Jing
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xuan Wu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau SAR, China
| | - Fu Peng
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Department of Pharmacology, Sichuan University, Chengdu, China
- Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Dan Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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14
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Xu ZH, Ma MH, Li YQ, Li LL, Liu GH. Progress and expectation of stem cell therapy for diabetic wound healing. World J Clin Cases 2023; 11:506-513. [PMID: 36793646 PMCID: PMC9923865 DOI: 10.12998/wjcc.v11.i3.506] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 11/08/2022] [Accepted: 01/09/2023] [Indexed: 01/22/2023] Open
Abstract
Impaired wound healing presents great health risks to diabetics. Encouragingly, the current clinical successfully found out meaningful method to repair wound tissue, and stem cell therapy could be an effective method for diabetic wound healing with its ability to accelerate wound closure and avoid amputation. This minireview aims at introducing stem cell therapy for facilitating tissue repair in diabetic wounds, discussing the possible therapeutic mechanism and clinical application status and problems.
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Affiliation(s)
- Zhen-Han Xu
- Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510610, Guangdong Province, China
| | - Meng-Hui Ma
- Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510610, Guangdong Province, China
| | - Yan-Qing Li
- Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510610, Guangdong Province, China
| | - Li-Lin Li
- Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510610, Guangdong Province, China
| | - Gui-Hua Liu
- Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510610, Guangdong Province, China
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15
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Dama G, Du J, Zhu X, Liu Y, Lin J. Bone marrow-derived mesenchymal stem cells: A promising therapeutic option for the treatment of diabetic foot ulcers. Diabetes Res Clin Pract 2023; 195:110201. [PMID: 36493913 DOI: 10.1016/j.diabres.2022.110201] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 08/31/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022]
Abstract
Chronic wounds fail to heal through the three normal stages of healing (inflammatory, proliferative, and remodelling), resulting in a chronic tissue injury that is not repaired within the average time limit. Patients suffering from type 1 and type 2 diabetes are prone to develop diabetic foot ulcers (DFUs), which commonly develop into chronic wounds that are non treatable with conventional therapies. DFU develops due to various risk factors, such as peripheral neuropathy, peripheral vascular disease, arterial insufficiency, foot deformities, trauma and impaired resistance to infection. DFUs have gradually become a major problem in the health care system worldwide. In this review, we not only focus on the pathogenesis of DFU but also comprehensively summarize the outcomes of preclinical and clinical studies thus far and the potential therapeutic mechanism of bone marrow-derived mesenchymal stem cells (BMSCs) for the treatment of DFU. Based on the published results, BMSC transplantation can contribute to wound healing through growth factor secretion, anti-inflammation, differentiation into tissue-specific cells, neovascularization, re-epithelialization and angiogenesis in DFUs. Moreover, clinical trials showed that BMSC treatment in patients with diabetic ulcers improved ulcer healing and the ankle-brachial index, ameliorated pain scores, and enhanced claudication walking distances with no reported complications. In conclusion, although BMSC transplantation exhibits promising therapeutic potential in DFU treatment, additional studies should be performed to confirm their efficacy and long-term safety in DFU patients.
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Affiliation(s)
- Ganesh Dama
- Stem Cell and Biotherapy Engineering Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China; Department of Community Health, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas, Malaysia
| | - Jiang Du
- Stem Cell and Biotherapy Engineering Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China; College of Medical Engineering, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China
| | - Xinxing Zhu
- Stem Cell and Biotherapy Engineering Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China; College of Medical Engineering, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China
| | - Yanli Liu
- Stem Cell and Biotherapy Engineering Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China; College of Life Sciences and Technology, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China.
| | - Juntang Lin
- Stem Cell and Biotherapy Engineering Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China; College of Medical Engineering, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China; College of Life Sciences and Technology, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China.
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16
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Mahmoudvand G, Karimi Rouzbahani A, Razavi ZS, Mahjoor M, Afkhami H. Mesenchymal stem cell therapy for non-healing diabetic foot ulcer infection: New insight. Front Bioeng Biotechnol 2023; 11:1158484. [PMID: 37122856 PMCID: PMC10133463 DOI: 10.3389/fbioe.2023.1158484] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 03/31/2023] [Indexed: 05/02/2023] Open
Abstract
Diabetic foot ulcer (DFU) is considered the most catastrophic complication of diabetes mellitus (DM), leading to repeated hospitalizations, infection, gangrene, and finally amputation of the limb. In patients suffering from diabetes mellitus, the wound-healing process is impaired due to various factors such as endothelial dysfunction and synthesis of advanced glycation end-products, hence, conventional therapeutic interventions might not be effective. With increasing therapeutic applications of mesenchymal stem cells (MSCs) in recent years, their potential as a method for improving the wound-healing process has gained remarkable attention. In this field, mesenchymal stem cells exert their beneficial effects through immunomodulation, differentiation into the essential cells at the site of ulcers, and promoting angiogenesis, among others. In this article, we review cellular and molecular pathways through which mesenchymal stem cell therapy reinforces the healing process in non-healing Diabetic foot ulcers.
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Affiliation(s)
- Golnaz Mahmoudvand
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Arian Karimi Rouzbahani
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Zahra Sadat Razavi
- Physiology Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohamad Mahjoor
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Afkhami
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
- *Correspondence: Hamed Afkhami,
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17
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Bellei B, Migliano E, Picardo M. Therapeutic potential of adipose tissue-derivatives in modern dermatology. Exp Dermatol 2022; 31:1837-1852. [PMID: 35102608 DOI: 10.1111/exd.14532] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/24/2022] [Accepted: 01/28/2022] [Indexed: 12/14/2022]
Abstract
Stem cell-mediated therapies in combination with biomaterial and growth factor-based approaches in regenerative medicine are rapidly evolving with increasing application beyond the dermatologic field. Adipose-derived stem cells (ADSCs) are the more frequently used adult stem cells due to their abundance and easy access. In the case of volumetric defects, adipose tissue can take the shape of defects, restoring the volume and enhancing the regeneration of receiving tissue. When regenerative purposes prevail on volume restoration, the stromal vascular fraction (SVF) rich in staminal cells, purified mesenchymal stem cells (MSCs) or their cell-free derivatives grafting are favoured. The therapeutic efficacy of acellular approaches is explained by the fact that a significant part of the natural propensity of stem cells to repair damaged tissue is ascribable to their secretory activity that combines mitogenic factors, cytokines, chemokines and extracellular matrix components. Therefore, the secretome's ability to modulate multiple targets simultaneously demonstrated preclinical and clinical efficacy in reversing pathological mechanisms of complex conditions such atopic dermatitis (AD), vitiligo, psoriasis, acne and Lichen sclerosus (LS), non-resolving wounds and alopecia. This review analysing both in vivo and in vitro models gives an overview of the clinical relevance of adipose tissue-derivatives such as autologous fat graft, stromal vascular fraction, purified stem cells and secretome for skin disorders application. Finally, we highlighted the major disease-specific limitations and the future perspective in this field.
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Affiliation(s)
- Barbara Bellei
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Rome, Italy
| | - Emilia Migliano
- Department of Plastic and Regenerative Surgery, San Gallicano Dermatological Institute, IRCCS, Rome, Italy
| | - Mauro Picardo
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Rome, Italy
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18
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Oxidative Stress in Ageing and Chronic Degenerative Pathologies: Molecular Mechanisms Involved in Counteracting Oxidative Stress and Chronic Inflammation. Int J Mol Sci 2022; 23:ijms23137273. [PMID: 35806275 PMCID: PMC9266760 DOI: 10.3390/ijms23137273] [Citation(s) in RCA: 163] [Impact Index Per Article: 54.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 06/24/2022] [Accepted: 06/24/2022] [Indexed: 12/17/2022] Open
Abstract
Ageing and chronic degenerative pathologies demonstrate the shared characteristics of high bioavailability of reactive oxygen species (ROS) and oxidative stress, chronic/persistent inflammation, glycation, and mitochondrial abnormalities. Excessive ROS production results in nucleic acid and protein destruction, thereby altering the cellular structure and functional outcome. To stabilise increased ROS production and modulate oxidative stress, the human body produces antioxidants, “free radical scavengers”, that inhibit or delay cell damage. Reinforcing the antioxidant defence system and/or counteracting the deleterious repercussions of immoderate reactive oxygen and nitrogen species (RONS) is critical and may curb the progression of ageing and chronic degenerative syndromes. Various therapeutic methods for ROS and oxidative stress reduction have been developed. However, scientific investigations are required to assess their efficacy. In this review, we summarise the interconnected mechanism of oxidative stress and chronic inflammation that contributes to ageing and chronic degenerative pathologies, including neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), cardiovascular diseases CVD, diabetes mellitus (DM), and chronic kidney disease (CKD). We also highlight potential counteractive measures to combat ageing and chronic degenerative diseases.
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19
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Bellei B, Migliano E, Picardo M. Research update of adipose tissue-based therapies in regenerative dermatology. Stem Cell Rev Rep 2022; 18:1956-1973. [PMID: 35230644 DOI: 10.1007/s12015-022-10328-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/01/2022] [Indexed: 12/09/2022]
Abstract
Mesenchymal stromal/stem cells (MSCs) have a spontaneous propensity to support tissue homeostasis and regeneration. Among the several sources of MSCs, adipose-derived tissue stem cells (ADSCs) have received major interest due to the higher mesenchymal stem cells concentration, ease, and safety of access. However, since a significant part of the natural capacity of ADSCs to repair damaged tissue is ascribable to their secretory activity that combines mitogenic factors, cytokines, chemokines, lipids, and extracellular matrix components, several studies focused on cell-free strategies. Furthermore, adipose cell-free derivatives are becoming more attractive especially for non-volumizing purposes, such as most dermatological conditions. However, when keratinocytes, fibroblasts, melanocytes, adipocytes, and hair follicle cells might not be locally sourced, graft of materials containing concentrated ADSCs is preferred. The usage of extracellular elements of adipose tissue aims to promote a self-autonomous regenerative microenvironment in the receiving area restoring physiological homeostasis. Hence, ADSCs or their paracrine activity are currently being studied in several dermatological settings including wound healing, skin fibrosis, burn, and aging.The present work analyzing both preclinical and clinical experiences gives an overview of the efficacy of adipose tissue-derivatives like autologous fat, the stromal vascular fraction (SVF), purified ADSCs, secretome and extracellular matrix graft in the field of regenerative medicine for the skin.
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Affiliation(s)
- Barbara Bellei
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144, Rome, Italy.
| | - Emilia Migliano
- Department of Plastic and Reconstructive Surgery, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Mauro Picardo
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144, Rome, Italy
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20
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Yu Q, Qiao GH, Wang M, Yu L, Sun Y, Shi H, Ma TL. Stem Cell-Based Therapy for Diabetic Foot Ulcers. Front Cell Dev Biol 2022; 10:812262. [PMID: 35178389 PMCID: PMC8844366 DOI: 10.3389/fcell.2022.812262] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 01/04/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic foot ulcer has become a worldwide clinical medical challenge as traditional treatments are not effective enough to reduce the amputation rate. Therefore, it is of great social significance to deeply study the pathogenesis and biological characteristics of the diabetic foot, explore new treatment strategies and promote their application. Stem cell-based therapy holds tremendous promise in the field of regenerative medicine, and its mechanisms include promoting angiogenesis, ameliorating neuroischemia and inflammation, and promoting collagen deposition. Studying the specific molecular mechanisms of stem cell therapy for diabetic foot has an important role and practical clinical significance in maximizing the repair properties of stem cells. In addition, effective application modalities are also crucial in order to improve the survival and viability of stem cells at the wound site. In this paper, we reviewed the specific molecular mechanisms of stem cell therapy for diabetic foot and the extended applications of stem cells in recent years, with the aim of contributing to the development of stem cell-based therapy in the repair of diabetic foot ulcers.
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Affiliation(s)
- Qian Yu
- Department of Hepatology, Songjiang Hospital Affiliated to Nanjing Medical University, Shanghai, China
| | - Guo-Hong Qiao
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Min Wang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Li Yu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yaoxiang Sun
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Hui Shi
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China.,Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Tie-Liang Ma
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
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21
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Ormazabal V, Nova-Lampeti E, Rojas D, Zúñiga FA, Escudero C, Lagos P, Moreno A, Pavez Y, Reyes C, Yáñez M, Vidal M, Cabrera-Vives G, Oporto K, Aguayo C. Secretome from Human Mesenchymal Stem Cells-Derived Endothelial Cells Promotes Wound Healing in a Type-2 Diabetes Mouse Model. Int J Mol Sci 2022; 23:ijms23020941. [PMID: 35055129 PMCID: PMC8779848 DOI: 10.3390/ijms23020941] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 12/06/2021] [Accepted: 12/10/2021] [Indexed: 12/17/2022] Open
Abstract
Tissue regeneration is often impaired in patients with metabolic disorders such as diabetes mellitus and obesity, exhibiting reduced wound repair and limited regeneration capacity. We and others have demonstrated that wound healing under normal metabolic conditions is potentiated by the secretome of human endothelial cell-differentiated mesenchymal stem cells (hMSC-EC). However, it is unknown whether this effect is sustained under hyperglycemic conditions. In this study, the wound healing effect of secretomes from undifferentiated human mesenchymal stem cells (hMSC) and hMSC-EC in a type-2 diabetes mouse model was analyzed. hMSC were isolated from human Wharton’s jelly and differentiated into hMSC-EC. hMSC and hMSC-EC secretomes were analyzed and their wound healing capacity in C57Bl/6J mice fed with control (CD) or high fat diet (HFD) was evaluated. Our results showed that hMSC-EC secretome enhanced endothelial cell proliferation and wound healing in vivo when compared with hMSC secretome. Five soluble proteins (angiopoietin-1, angiopoietin-2, Factor de crecimiento fibroblástico, Matrix metallopeptidase 9, and Vascular Endothelial Growth Factor) were enriched in hMSC-EC secretome in comparison to hMSC secretome. Thus, the five recombinant proteins were mixed, and their pro-healing property was evaluated in vitro and in vivo. Functional analysis demonstrated that a cocktail of these proteins enhanced the wound healing process similar to hMSC-EC secretome in HFD mice. Overall, our results show that hMSC-EC secretome or a combination of specific proteins enriched in the hMSC-EC secretome enhanced wound healing process under hyperglycemic conditions.
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Affiliation(s)
- Valeska Ormazabal
- Department of Pharmacology, Faculty of Biological Sciences, Universidad de Concepción, Concepción 4030000, Chile; (V.O.); (P.L.)
| | - Estefanía Nova-Lampeti
- Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, Universidad de Concepción, Concepción 4030000, Chile; (E.N.-L.); (F.A.Z.); (A.M.); (Y.P.); (C.R.); (K.O.)
| | - Daniela Rojas
- Department of Animal Pathology, Faculty of Veterinary Sciences, Universidad de Concepción, Chillan 3787000, Chile;
| | - Felipe A. Zúñiga
- Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, Universidad de Concepción, Concepción 4030000, Chile; (E.N.-L.); (F.A.Z.); (A.M.); (Y.P.); (C.R.); (K.O.)
| | - Carlos Escudero
- Vascular Physiology Laboratory, Department of Basic Sciences, Universidad del Bio-Bio, Chillan 3787000, Chile;
- Group of Research and Innovation in Vascular Health (GRIVAS Health), Chillan 3787000, Chile
| | - Paola Lagos
- Department of Pharmacology, Faculty of Biological Sciences, Universidad de Concepción, Concepción 4030000, Chile; (V.O.); (P.L.)
| | - Alexa Moreno
- Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, Universidad de Concepción, Concepción 4030000, Chile; (E.N.-L.); (F.A.Z.); (A.M.); (Y.P.); (C.R.); (K.O.)
| | - Yanara Pavez
- Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, Universidad de Concepción, Concepción 4030000, Chile; (E.N.-L.); (F.A.Z.); (A.M.); (Y.P.); (C.R.); (K.O.)
| | - Camila Reyes
- Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, Universidad de Concepción, Concepción 4030000, Chile; (E.N.-L.); (F.A.Z.); (A.M.); (Y.P.); (C.R.); (K.O.)
| | - Milly Yáñez
- Department of Pathological Anatomy, Las Higueras Hospital, Talcahuano 4030000, Chile;
| | - Mabel Vidal
- Department of Computer Science, Faculty of Engineering, Universidad de Concepción, Concepción 4030000, Chile; (M.V.); (G.C.-V.)
| | - Guillermo Cabrera-Vives
- Department of Computer Science, Faculty of Engineering, Universidad de Concepción, Concepción 4030000, Chile; (M.V.); (G.C.-V.)
| | - Katherine Oporto
- Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, Universidad de Concepción, Concepción 4030000, Chile; (E.N.-L.); (F.A.Z.); (A.M.); (Y.P.); (C.R.); (K.O.)
| | - Claudio Aguayo
- Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, Universidad de Concepción, Concepción 4030000, Chile; (E.N.-L.); (F.A.Z.); (A.M.); (Y.P.); (C.R.); (K.O.)
- Group of Research and Innovation in Vascular Health (GRIVAS Health), Chillan 3787000, Chile
- Correspondence: ; Tel.: +56-41-2207196
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Muralikumar M, Manoj Jain S, Ganesan H, Duttaroy AK, Pathak S, Banerjee A. Current understanding of the mesenchymal stem cell-derived exosomes in cancer and aging. BIOTECHNOLOGY REPORTS (AMSTERDAM, NETHERLANDS) 2021; 31:e00658. [PMID: 34377681 PMCID: PMC8327488 DOI: 10.1016/j.btre.2021.e00658] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 07/01/2021] [Accepted: 07/08/2021] [Indexed: 02/07/2023]
Abstract
Mesenchymal stem cells (MSCs) are being widely researched upon for several years with translational application in regenerative medicine. Many studies acknowledged trophic factors from MSCs, attenuating dreadful ailments. The beneficial properties of MSCs are attributed to their secretion of paracrine factors as extracellular vesicles/ exosomes in the tissue microenvironment. Exosomes are nano-sized vesicles involved in genetic material transportation and intercellular communication. Exosomes have been recently reported to play a role in cell-free therapy in treating many diseases like cancer and aging and are reported in regulating tumor cell fate. This review highlights the recent advances and current understanding in assessing mesenchymal stem cell-derived exosomes for possible cell-free therapy. The sources and composition of exosomes, drug delivery effectiveness, immunomodulatory property, therapeutic advances in cancer, and aging targeting exosomes as cargo or its effect to moderate the tissue microenvironment are also discussed. We summarize the regenerative mechanisms induced by MSCs derived exosomes.
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Affiliation(s)
- Makalakshmi Muralikumar
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, Tamil Nadu, India
| | - Samatha Manoj Jain
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, Tamil Nadu, India
| | - Harsha Ganesan
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, Tamil Nadu, India
| | - Asim K. Duttaroy
- Department of Nutrition, IMB, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Surajit Pathak
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, Tamil Nadu, India
| | - Antara Banerjee
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, Tamil Nadu, India
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Yao A, Li Z, Lyu J, Yu L, Wei S, Xue L, Wang H, Chen GQ. On the nutritional and therapeutic effects of ketone body D-β-hydroxybutyrate. Appl Microbiol Biotechnol 2021; 105:6229-6243. [PMID: 34415393 PMCID: PMC8377336 DOI: 10.1007/s00253-021-11482-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 12/31/2022]
Abstract
Abstract d-β-hydroxybutyrate (d-3HB), a monomer of microbial polyhydroxybutyrate (PHB), is also a natural ketone body produced during carbohydrate deprivation to provide energy to the body cells, heart, and brain. In recent years, increasing evidence demonstrates that d-3HB can induce pleiotropic effects on the human body which are highly beneficial for improving physical and metabolic health. Conventional ketogenic diet (KD) or exogenous ketone salts (KS) and esters (KE) have been used to increase serum d-3HB level. However, strict adaptation to the KD was often associated with poor patient compliance, while the ingestion of KS caused gastrointestinal distresses due to excessive consumption of minerals. As for ingestion of KE, subsequent degradation is required before releasing d-3HB for absorption, making these methods somewhat inferior. This review provides novel insights into a biologically synthesized d-3HB (d-3-hydroxybutyric acid) which can induce a faster increase in plasma d-3HB compared to the use of KD, KS, or KE. It also emphasizes on the most recent applications of d-3HB in different fields, including its use in improving exercise performance and in treating metabolic or age-related diseases. Ketones may become a fourth micro-nutrient that is necessary to the human body along with carbohydrates, proteins, and fats. Indeed, d-3HB being a small molecule with multiple signaling pathways within the body exhibits paramount importance in mitigating metabolic and age-related diseases. Nevertheless, specific dose–response relationships and safety margins of using d-3HB remain to be elucidated with more research. Key points • d-3HB induces pleiotropic effects on physical and metabolic health. • Exogenous ketone supplements are more effective than ketogenic diet. • d-3HB as a ketone supplement has long-term healthy impact.
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Affiliation(s)
- Aliya Yao
- MedPHA Bioscience Co. Ltd., Traditional Chinese Medicine Science and Technology Industrial Park of Co-Operation Between Guangdong and Macau, Building No.103, 36 Doukou Rd, Hengqin District, Zhuhai, 519030, Guangdong Province, China
| | - Zihua Li
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China
| | - Jinyan Lyu
- MedPHA Bioscience Co. Ltd., Traditional Chinese Medicine Science and Technology Industrial Park of Co-Operation Between Guangdong and Macau, Building No.103, 36 Doukou Rd, Hengqin District, Zhuhai, 519030, Guangdong Province, China
| | - Liusong Yu
- MedPHA Bioscience Co. Ltd., Traditional Chinese Medicine Science and Technology Industrial Park of Co-Operation Between Guangdong and Macau, Building No.103, 36 Doukou Rd, Hengqin District, Zhuhai, 519030, Guangdong Province, China
| | - Situ Wei
- MedPHA Bioscience Co. Ltd., Traditional Chinese Medicine Science and Technology Industrial Park of Co-Operation Between Guangdong and Macau, Building No.103, 36 Doukou Rd, Hengqin District, Zhuhai, 519030, Guangdong Province, China
| | - Lingyun Xue
- MedPHA Bioscience Co. Ltd., Traditional Chinese Medicine Science and Technology Industrial Park of Co-Operation Between Guangdong and Macau, Building No.103, 36 Doukou Rd, Hengqin District, Zhuhai, 519030, Guangdong Province, China
| | - Hui Wang
- Department of Colorectal Surgery, Guangdong Province Biomedical Material Conversion and Evaluation Engineering Technology Center, Institute of Biomedical Innovation, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, Guangdong Province, China
| | - Guo-Qiang Chen
- MedPHA Bioscience Co. Ltd., Traditional Chinese Medicine Science and Technology Industrial Park of Co-Operation Between Guangdong and Macau, Building No.103, 36 Doukou Rd, Hengqin District, Zhuhai, 519030, Guangdong Province, China. .,School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China. .,School of Life Sciences and Dept Chemical Engineering, Center for Synthetic and Systems Biology (CSSB), Tsinghua University, Beijing, 100084, China.
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The Role of MSC in Wound Healing, Scarring and Regeneration. Cells 2021; 10:cells10071729. [PMID: 34359898 PMCID: PMC8305394 DOI: 10.3390/cells10071729] [Citation(s) in RCA: 212] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/02/2021] [Accepted: 07/03/2021] [Indexed: 02/06/2023] Open
Abstract
Tissue repair and regeneration after damage is not completely understood, and current therapies to support this process are limited. The wound healing process is associated with cell migration and proliferation, extracellular matrix remodeling, angiogenesis and re-epithelialization. In normal conditions, a wound will lead to healing, resulting in reparation of the tissue. Several risk factors, chronic inflammation, and some diseases lead to a deficient wound closure, producing a scar that can finish with a pathological fibrosis. Mesenchymal stem/stromal cells (MSCs) are widely used for their regenerative capacity and their possible therapeutically potential. Derived products of MSCs, such as exosomes or extravesicles, have shown a therapeutic potential similar to MSCs, and these cell-free products may be interesting in clinics. MSCs or their derivative products have shown paracrine beneficial effects, regulating inflammation, modifying the fibroblast activation and production of collagen and promoting neovascularization and re-epithelialization. This review describes the effects of MSCs and their derived products in each step of the wound repair process. As well, it reviews the pre-clinical and clinical use of MSCs to benefit in skin wound healing in diabetic associated wounds and in pathophysiological fibrosis.
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Topical Application of Conditioned Medium from Hypoxically Cultured Amnion-Derived Mesenchymal Stem Cells Promotes Wound Healing in Diabetic Mice. Plast Reconstr Surg 2021; 147:1342-1352. [PMID: 34019504 DOI: 10.1097/prs.0000000000007993] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Mesenchymal stem cells or their conditioned medium improve chronic wound healing, and their effect is enhanced by hypoxia. Diabetic foot ulcers are chronic wounds characterized by abnormal and delayed healing, which frequently require amputation. The authors evaluated the effect of topical application of conditioned medium from hypoxically cultured amnion-derived mesenchymal stem cells on wound healing in diabetic mice. METHODS Amnion-derived mesenchymal stem cells were cultured under 21% oxygen to prepare normoxic conditioned medium and under 1% oxygen to prepare hypoxic conditioned medium. Hydrogels containing standard medium, normoxic conditioned medium, or hypoxic conditioned medium were topically applied to excisional wounds of mice with streptozotocin-induced diabetes. Ulcer tissues were harvested on day 9; immunohistochemical and quantitative polymerase chain reaction analyses were performed to analyze angiogenesis, inflammatory cell infiltration, and expression levels of inflammation-related genes. RESULTS Hypoxic conditioned medium significantly enhanced wound closure, increased capillary density and epithelization, and reduced macrophage infiltration. It also tended to reduce the infiltration of neutrophils and enhance the infiltration of regulatory T cells; it showed a tendency to downregulate the expression of the inflammation-related genes interleukin-1β, interleukin-6, chemokine ligand 1, and chemokine ligand 2. Normoxic conditioned medium exhibited similar effects, although they were of lesser magnitude than those of hypoxic conditioned medium. CONCLUSIONS Hydrogels containing hypoxically cultured, amnion-derived mesenchymal stem cell conditioned medium accelerated wound healing in diabetic mice by enhancing angiogenesis, accelerating epithelization, and suppressing inflammation. Therefore, topical application of amnion mesenchymal stem cell-derived hypoxic conditioned medium could be a novel treatment for diabetic foot ulcers.
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Yan J, Liang J, Cao Y, El Akkawi MM, Liao X, Chen X, Li C, Li K, Xie G, Liu H. Efficacy of topical and systemic transplantation of mesenchymal stem cells in a rat model of diabetic ischemic wounds. Stem Cell Res Ther 2021; 12:220. [PMID: 33789742 PMCID: PMC8010295 DOI: 10.1186/s13287-021-02288-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 03/15/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) exert positive effects in chronic wounds. However, critical parameters, such as the most effective administration routes, remain unclear. Accordingly, the purpose of this study was to compare the effects of topical and systemic transplantation MSCs on diabetic ischemic wound healing and explored the underlying mechanisms. METHOD A diabetic ischemic wound model was created on the dorsal foot of type 2 diabetes mellitus (T2DM) rat. Bone marrow-derived mesenchymal stem cells (BM-MSCs) were administered via two routes: topical injection and intravenous (IV) infusion. Wound healing outcomes and blood glucose level were assessed dynamically. Meanwhile, blood flow recovery was evaluated in ischemic gastrocnemius muscles. The homing and transdifferentiation of mKate2-labeled BM-MSCs were assessed by fluorescence imaging and immunohistochemistry (IHC) analysis. RESULT Both topical and systemic treatments had a positive effect on the diabetic ischemic wound showing a significant reduction in wound area at day 14. Histological results showed an increase in the length of epithelial edges, collagen content, microvessel density in the wound bed, and a higher expression of vascular endothelial growth factor (VEGF). Meanwhile, systemic administration can ameliorate hyperglycemia and improve the blood perfusion of the ischemic hindlimb. BM-MSCs administered systemically were found distributed in wounded tissue and transdifferentiated into endothelial cells. Furthermore, BM-MSCs stimulated angiogenesis at wound sites by downregulating phosphatase and tensin homolog (PTEN) and activation of AKT signaling pathway. CONCLUSIONS The results demonstrated that both transplantation delivery method (topical and systemic) of BM-MSCs accelerated wound healing remarkably under pathological conditions. Nevertheless, systemic administration has the potential to ameliorate hyperglycemia and repair the damaged tissue.
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Affiliation(s)
- Jianxin Yan
- Department of Plastic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510630 People’s Republic of China
- Innovative Technology Research Institute of Plastic Surgery, Guangzhou, 510630 People’s Republic of China
- Key Laboratory of Regenerative Medicine, Ministry of Education, Guangzhou, 510632 People’s Republic of China
| | - Jiaji Liang
- Department of Plastic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510630 People’s Republic of China
- Innovative Technology Research Institute of Plastic Surgery, Guangzhou, 510630 People’s Republic of China
- Key Laboratory of Regenerative Medicine, Ministry of Education, Guangzhou, 510632 People’s Republic of China
| | - Yingxuan Cao
- Department of Plastic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510630 People’s Republic of China
- Innovative Technology Research Institute of Plastic Surgery, Guangzhou, 510630 People’s Republic of China
- Key Laboratory of Regenerative Medicine, Ministry of Education, Guangzhou, 510632 People’s Republic of China
| | - Mariya M. El Akkawi
- Department of Plastic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510630 People’s Republic of China
- Innovative Technology Research Institute of Plastic Surgery, Guangzhou, 510630 People’s Republic of China
- Key Laboratory of Regenerative Medicine, Ministry of Education, Guangzhou, 510632 People’s Republic of China
| | - Xuan Liao
- Department of Plastic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510630 People’s Republic of China
- Innovative Technology Research Institute of Plastic Surgery, Guangzhou, 510630 People’s Republic of China
- Key Laboratory of Regenerative Medicine, Ministry of Education, Guangzhou, 510632 People’s Republic of China
| | - Xiaojia Chen
- Department of Cell Biology & Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632 People’s Republic of China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou, 510632 People’s Republic of China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou, 510632 People’s Republic of China
- National Engineering Research Center of Genetic Medicine, Guangzhou, 510632 People’s Republic of China
| | - Chengzhi Li
- Department of Interventional Radiology and Vascular Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510630 People’s Republic of China
| | - Kecheng Li
- Department of Plastic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510630 People’s Republic of China
- Innovative Technology Research Institute of Plastic Surgery, Guangzhou, 510630 People’s Republic of China
- Key Laboratory of Regenerative Medicine, Ministry of Education, Guangzhou, 510632 People’s Republic of China
| | - Guanghui Xie
- Department of Plastic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510630 People’s Republic of China
- Innovative Technology Research Institute of Plastic Surgery, Guangzhou, 510630 People’s Republic of China
- Key Laboratory of Regenerative Medicine, Ministry of Education, Guangzhou, 510632 People’s Republic of China
| | - Hongwei Liu
- Department of Plastic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510630 People’s Republic of China
- Innovative Technology Research Institute of Plastic Surgery, Guangzhou, 510630 People’s Republic of China
- Key Laboratory of Regenerative Medicine, Ministry of Education, Guangzhou, 510632 People’s Republic of China
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Mesenchymal Stem Cell-derived Extracellular Vesicles for Skin Wound Healing. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1310:495-507. [PMID: 33834447 DOI: 10.1007/978-981-33-6064-8_18] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Skin is vulnerable to various external insults such as burn, severe injury, or inflammation, which necessitates a better strategy for wound repair. Mesenchymal stem cells (MSCs) can self-renew and differentiate into various supporting tissues including cartilage, bone, muscle, and adipose tissue. Along with their unique multipotent capacity, they secrete various paracrine mediators such as growth factors, cytokines, and membrane-enclosed particles called extracellular vesicles (EVs). Herein, we discussed the general traits of EVs such as cell-to-cell communicator, and highlighted the recent preclinical outcomes, with a focus on the application of MSC-derived EVs in wound repair. This chapter provides insights into developing novel strategies for skin wound healing in a cell-free manner.
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Chen S, He Z, Xu J. Application of adipose-derived stem cells in photoaging: basic science and literature review. Stem Cell Res Ther 2020; 11:491. [PMID: 33225962 PMCID: PMC7682102 DOI: 10.1186/s13287-020-01994-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 10/23/2020] [Indexed: 12/13/2022] Open
Abstract
Photoaging is mainly induced by continuous exposure to sun light, causing multiple unwanted skin characters and accelerating skin aging. Adipose-derived stem cells(ADSCs) are promising in supporting skin repair because of their significant antioxidant capacity and strong proliferation, differentiation, and migration ability, as well as their enriched secretome containing various growth factors and cytokines. The identification of the mechanisms by which ADSCs perform these functions for photoaging has great potential to explore therapeutic applications and combat skin aging. We also review the basic mechanisms of UV-induced skin aging and recent improvement in pre-clinical applications of ADSCs associated with photoaging. Results showed that ADSCs are potential to address photoaging problem and might treat skin cancer. Compared with ADSCs alone, the secretome-based approaches and different preconditionings of ADSCs are more promising to overcome the current limitations and enhance the anti-photoaging capacity.
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Affiliation(s)
- Shidie Chen
- Department of Plastic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, China
| | - Zhigang He
- Department of Plastic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, China.
| | - Jinghong Xu
- Department of Plastic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, China.
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Combined Transplantation of Mesenchymal Stem Cells and Endothelial Colony-Forming Cells Accelerates Refractory Diabetic Foot Ulcer Healing. Stem Cells Int 2020; 2020:8863649. [PMID: 33061991 PMCID: PMC7545465 DOI: 10.1155/2020/8863649] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 07/19/2020] [Accepted: 08/26/2020] [Indexed: 12/17/2022] Open
Abstract
Background This study is aimed at investigating the effect of combined transplantation of umbilical cord mesenchymal stem cells (UCMSCs) and umbilical cord blood-derived endothelial colony-forming cells (ECFCs) on diabetic foot ulcer healing and at providing a novel therapy for chronic diabetic foot ulcer. Methods We reported the treatment of refractory diabetic foot ulcers in twelve patients. Among them, five patients had two or more wounds; thus, one wound in the same patient was treated with cell injection, and other wounds were regarded as self-controls. The remaining seven patients had only one wound; therefore, the difference between the area of wound before and after treatment was estimated. The UCMSCs and ECFCs were injected into the wound along with topically applied hyaluronic acid (HA). Results In this report, we compared the healing rate of multiple separate wounds in the same foot of the same patient: one treated with cell injection combined with topically applied HA-based hydrogel and was later covered by the hydrocolloid dressings, while the self-control wounds were only treated with conventional therapy and covered by the hydrocolloid dressings. The wound underwent cell injection showed accelerated healing in comparison to control wound within the first week after treatment. In other diabetic patients with only one refractory wound, the healing rate after cell transplantation was significantly faster than that before injection. Two large wounds healed without needing skin grafts after combination therapy of cell injection and HA. After four weeks of combination treatment, wound closure was reached in six patients, and the wounds of the other six patients were significantly reduced in size. Conclusions Our study suggests that the combination of UCMSCs, ECFCs, and HA can safely synergize the accelerated healing of refractory diabetic foot ulcers.
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Nilforoushzadeh MA, Khodadadi Yazdi M, Baradaran Ghavami S, Farokhimanesh S, Mohammadi Amirabad L, Zarrintaj P, Saeb MR, Hamblin MR, Zare M, Mozafari M. Mesenchymal Stem Cell Spheroids Embedded in an Injectable Thermosensitive Hydrogel: An In Situ Drug Formation Platform for Accelerated Wound Healing. ACS Biomater Sci Eng 2020; 6:5096-5109. [PMID: 33455261 DOI: 10.1021/acsbiomaterials.0c00988] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The ability of mesenchymal stem cells (MSCs) to enhance cutaneous wound healing has been well established. Extensive expansion of cells to reach sufficient cell numbers for regenerating tissues has always limited cell-based therapies. An ingenious solution to address this challenge is to develop a strategy to increase the immunomodulatory effects of MSCs without expanding them. In this study, we employed a simple characteristic of cells. It was observed that an optimized three-dimensional (3D) MSC culture in spheroid forms significantly improved their paracrine effects. An electrospray (ES) encapsulation apparatus was used to encapsulate individual or 3D spheroid MSCs into microscale alginate beads (microbeads). Furthermore, alginate microbeads were embedded in an injectable thermosensitive hydrogel matrix, which gels at skin temperature. The hydrogel fills and seals the wounds cavities, maintains high humidity at the wound area, absorbs exudate, and fixes microbeads, protecting them from direct contact with the harsh wound environment. In vitro investigations revealed that secretion of interleukin 10 (IL-0) and transforming growth factor β1 (TGF-β1) gene was gradually enhanced, providing a delivery platform for prolonged release of bioactive molecules. In vivo study on full-thickness wounds showed granulation and re-epithelialization, only after 7 days. Moreover, increased expression of α-smooth muscle actin (α-SMA) in the first 14 days after treatment ensured wound contraction. Besides, a gradual decrease in α-SMA secretion resulted in reduced scar formation. Well-organized collagen fibrils and high expression of the angiogenesis biomarker CD31 confirmed the promoting effect of the hydrogel on the wound-healing process. The proposed wound-dressing system would potentially be used in scalable and effective cell-based wound therapies.
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Affiliation(s)
| | | | - Shaghayegh Baradaran Ghavami
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samila Farokhimanesh
- Department of Biotechnology, Applied Biophotonics Research Center, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | | | - Payam Zarrintaj
- School of Chemical Engineering, Oklahoma State University, 420 Engineering North, Stillwater, Oklahoma 74078, United States
| | - Mohammad Reza Saeb
- Center of Excellence in Electrochemistry, School of Chemistry, College of Science, University of Tehran, Tehran, Iran
| | - Michael R Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts 02114, United States
- Department of Dermatology, Harvard Medical School, Boston, Massachusetts 02115, United States
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
| | - Mehrak Zare
- Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Mozafari
- Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
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De Gregorio C, Contador D, Díaz D, Cárcamo C, Santapau D, Lobos-Gonzalez L, Acosta C, Campero M, Carpio D, Gabriele C, Gaspari M, Aliaga-Tobar V, Maracaja-Coutinho V, Ezquer M, Ezquer F. Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice. Stem Cell Res Ther 2020; 11:168. [PMID: 32357914 PMCID: PMC7195803 DOI: 10.1186/s13287-020-01680-0] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 03/31/2020] [Accepted: 04/15/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Diabetic polyneuropathy (DPN) is the most common and early developing complication of diabetes mellitus, and the key contributor for foot ulcers development, with no specific therapies available. Different studies have shown that mesenchymal stem cell (MSC) administration is able to ameliorate DPN; however, limited cell survival and safety reasons hinder its transfer from bench to bedside. MSCs secrete a broad range of antioxidant, neuroprotective, angiogenic, and immunomodulatory factors (known as conditioned medium), which are all decreased in the peripheral nerves of diabetic patients. Furthermore, the abundance of these factors can be boosted in vitro by incubating MSCs with a preconditioning stimulus, enhancing their therapeutic efficacy. We hypothesize that systemic administration of conditioned medium derived from preconditioned MSCs could reverse DPN and prevent foot ulcer formation in a mouse model of type II diabetes mellitus. METHODS Diabetic BKS db/db mice were treated with systemic administration of conditioned medium derived from preconditioned human MSCs; conditioned medium derived from non-preconditioned MSCs or vehicle after behavioral signs of DPN was already present. Conditioned medium or vehicle administration was repeated every 2 weeks for a total of four administrations, and several functional and structural parameters characteristic of DPN were evaluated. Finally, a wound was made in the dorsal surface of both feet, and the kinetics of wound closure, re-epithelialization, angiogenesis, and cell proliferation were evaluated. RESULTS Our molecular, electrophysiological, and histological analysis demonstrated that the administration of conditioned medium derived from non-preconditioned MSCs or from preconditioned MSCs to diabetic BKS db/db mice strongly reverts the established DPN, improving thermal and mechanical sensitivity, restoring intraepidermal nerve fiber density, reducing neuron and Schwann cell apoptosis, improving angiogenesis, and reducing chronic inflammation of peripheral nerves. Furthermore, DPN reversion induced by conditioned medium administration enhances the wound healing process by accelerating wound closure, improving the re-epithelialization of the injured skin and increasing blood vessels in the wound bed in a skin injury model that mimics a foot ulcer. CONCLUSIONS Studies conducted indicate that MSC-conditioned medium administration could be a novel cell-free therapeutic approach to reverse the initial stages of DPN, avoiding the risk of lower limb amputation triggered by foot ulcer formation and accelerating the wound healing process in case it occurs.
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Affiliation(s)
- Cristian De Gregorio
- Center for Regenerative Medicine, School of Medicine Clínica Alemana-Universidad del Desarrollo, Av. Las Condes 12438, Lo Barnechea, Santiago, Chile
| | - David Contador
- Center for Regenerative Medicine, School of Medicine Clínica Alemana-Universidad del Desarrollo, Av. Las Condes 12438, Lo Barnechea, Santiago, Chile
| | - Diego Díaz
- Center for Regenerative Medicine, School of Medicine Clínica Alemana-Universidad del Desarrollo, Av. Las Condes 12438, Lo Barnechea, Santiago, Chile
| | - Constanza Cárcamo
- Center for Regenerative Medicine, School of Medicine Clínica Alemana-Universidad del Desarrollo, Av. Las Condes 12438, Lo Barnechea, Santiago, Chile
| | - Daniela Santapau
- Center for Regenerative Medicine, School of Medicine Clínica Alemana-Universidad del Desarrollo, Av. Las Condes 12438, Lo Barnechea, Santiago, Chile
| | - Lorena Lobos-Gonzalez
- Center for Regenerative Medicine, School of Medicine Clínica Alemana-Universidad del Desarrollo, Av. Las Condes 12438, Lo Barnechea, Santiago, Chile
| | - Cristian Acosta
- Institute of Histology and Embryology of Mendoza (IHEM-CONICET), School of Medicine, Universidad Nacional de Cuyo, Mendoza, Argentina
| | - Mario Campero
- Department of Neurology & Neurosurgery, Hospital José Joaquín Aguirre, Universidad de Chile, Santiago, Chile
| | - Daniel Carpio
- Institute of Anatomy, Histology and Pathology, Universidad Austral de Chile, Valdivia, Chile
| | - Caterina Gabriele
- Research Center for Advanced Biochemistry and Molecular Biology, Department of Experimental and Clinical Medicine, University of Catanzaro, Catanzaro, Italy
| | - Marco Gaspari
- Research Center for Advanced Biochemistry and Molecular Biology, Department of Experimental and Clinical Medicine, University of Catanzaro, Catanzaro, Italy
| | - Victor Aliaga-Tobar
- Advanced Center for Chronic Diseases-ACCDiS, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile
| | - Vinicius Maracaja-Coutinho
- Advanced Center for Chronic Diseases-ACCDiS, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile
| | - Marcelo Ezquer
- Center for Regenerative Medicine, School of Medicine Clínica Alemana-Universidad del Desarrollo, Av. Las Condes 12438, Lo Barnechea, Santiago, Chile
| | - Fernando Ezquer
- Center for Regenerative Medicine, School of Medicine Clínica Alemana-Universidad del Desarrollo, Av. Las Condes 12438, Lo Barnechea, Santiago, Chile.
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Fui LW, Lok MPW, Govindasamy V, Yong TK, Lek TK, Das AK. Understanding the multifaceted mechanisms of diabetic wound healing and therapeutic application of stem cells conditioned medium in the healing process. J Tissue Eng Regen Med 2019; 13:2218-2233. [PMID: 31648415 DOI: 10.1002/term.2966] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Revised: 07/26/2019] [Accepted: 09/04/2019] [Indexed: 12/13/2022]
Abstract
Mesenchymal stem cells (MSCs) transplantation seems to be a promising new therapy for diabetic wound healing (DWH), and currently, arrays of MSCs from various sources ranging from umbilical, adipose to dental sources are available as a treatment modality for this disease. However, it now appears that only a fraction of transplanted cells actually assimilate and survive in host tissues suggesting that the major mechanism by which stem cells participate in tissue repair are most likely related to their secretome level. These include a wide range of growth factors, cytokines, and chemokines, which can be found from the conditioned medium (CM) used to culture the cells. Basic studies and preclinical work confirm that the therapeutic effect of CMs are comparable with the application of stem cells. This review describes in detail the wound healing process in diabetes and the cellular and biological factors that influence the process. Subsequently, through a comprehensive literature search of studies related to wound healing in diabetics, we aim to provide an overview of scientific merits of using MSCs-CM in the treatment of diabetic wound as well as the significant caveats, which restricts its potential use in clinical set-ups. To our best knowledge, this is one of the first review papers that collect the importance of stem cells as an alternative treatment to the DWH. We anticipate that the success of this treatment will have a significant clinical impact on diabetic wounds.
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Affiliation(s)
- Lai Woon Fui
- School of Bioscience, Faculty of Health & Medical Sciences, Taylor's University (Main Campus), Subang Jaya, Malaysia
| | | | - Vijayendran Govindasamy
- School of Bioscience, Faculty of Health & Medical Sciences, Taylor's University (Main Campus), Subang Jaya, Malaysia
| | - Then Kong Yong
- Department of Research and Development, CryoCord Sdn Bhd, Cyberjaya, Malaysia
| | - Then Khong Lek
- Department of Research and Development, CryoCord Sdn Bhd, Cyberjaya, Malaysia
| | - Anjan Kumar Das
- School of Medicine, Faculty of Health & Medical Sciences, Taylor's University (Main Campus), Subang Jaya, Malaysia
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Tan ST, Dosan R. Lessons From Epithelialization: The Reason Behind Moist Wound Environment. ACTA ACUST UNITED AC 2019. [DOI: 10.2174/1874372201913010034] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Wound healing consists of multiple structured mechanism and is influenced by various factors. Epithelialization is one of the major aspect in wound healing and inhibition of this mechanism will greatly impair wound healing. Epithelialization is a process where epithelial cells migrate upwards and repair the wounded area. This process is the most essential part in wound healing and occurs in proliferative phase of wound healing. Skin stem cells which reside in several locations of epidermis contribute in the re-epithelialization when the skin is damaged. Epithelialization process is activated by inflammatory signal and then keratinocyte migrate, differentiate and stratify to close the defect in the skin. Several theories of epithelialization model in wound healing have been proposed for decades and have shown the mechanism of epidermal cell migration during epithelialization even though the exact mechanism is still controversial. This process is known to be influenced by the wound environment where moist wound environment is preferred rather than dry wound environment. In dry wound environment, epithelialization is known to be inhibited because of scab or crust which is formed from dehydrated and dead cells. Moist wound environment enhances the epithelialization process by easier migration of epidermal cells, faster epithelialization, and prolonged presence of proteinases and growth factors. This article focuses on the epithelialization process in wound healing, epithelialization models, effects of wound environment on epithelialization and epithelialization as the basis for products that enhance wound healing.
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Päth G, Perakakis N, Mantzoros CS, Seufert J. Stem cells in the treatment of diabetes mellitus - Focus on mesenchymal stem cells. Metabolism 2019; 90:1-15. [PMID: 30342065 DOI: 10.1016/j.metabol.2018.10.005] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 09/25/2018] [Accepted: 10/14/2018] [Indexed: 12/14/2022]
Abstract
Diabetes mellitus type 1 and type 2 have become a global epidemic with dramatically increasing incidences. Poorly controlled diabetes is associated with severe life-threatening complications. Beside traditional treatment with insulin and oral anti-diabetic drugs, clinicians try to improve patient's care by cell therapies using embryonic stem cells (ESC), induced pluripotent stem cells (iPSC) and adult mesenchymal stem cells (MSC). ESC display a virtually unlimited plasticity, including the differentiation into insulin producing β-cells, but they raise ethical concerns and bear, like iPSC, the risk of tumours. IPSC may further inherit somatic mutations and remaining somatic transcriptional memory upon incomplete re-programming, but allow the generation of patient/disease-specific cell lines. MSC avoid such issues but have not been successfully differentiated into β-cells. Instead, MSC and their pericyte phenotypes outside the bone marrow have been recognized to secrete numerous immunomodulatory and tissue regenerative factors. On this account, the term 'medicinal signaling cells' has been proposed to define the new conception of a 'drug store' for injured tissues and to stay with the MSC nomenclature. This review presents the biological background and the resulting clinical potential and limitations of ESC, iPSC and MSC, and summarizes the current status quo of cell therapeutic concepts and trials.
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Affiliation(s)
- Günter Päth
- Division of Endocrinology and Diabetology, Department of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
| | - Nikolaos Perakakis
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Jochen Seufert
- Division of Endocrinology and Diabetology, Department of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
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Gkogkolou P, Sarna M, Sarna T, Paus R, Luger T, Böhm M. Protection of glucotoxicity by a tripeptide derivative of α‐melanocyte‐stimulating hormone in human epidermal keratinocytes. Br J Dermatol 2018; 180:836-848. [DOI: 10.1111/bjd.17125] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/21/2018] [Indexed: 12/21/2022]
Affiliation(s)
- P. Gkogkolou
- Department of Dermatology Laboratory for Neuroendocrinology of the Skin and Interdisciplinary Endocrinology University of Münster Von Esmarch‐Str. 58 48149 Münster Germany
| | - M. Sarna
- Department of Biophysics Faculty of Biochemistry, Biophysics and Biotechnology Jagiellonian University Cracow Poland
- Laboratory of Imaging and Atomic Force Spectroscopy Malopolska Centre of Biotechnology Jagiellonian University Cracow Poland
| | - T. Sarna
- Department of Biophysics Faculty of Biochemistry, Biophysics and Biotechnology Jagiellonian University Cracow Poland
- Laboratory of Imaging and Atomic Force Spectroscopy Malopolska Centre of Biotechnology Jagiellonian University Cracow Poland
| | - R. Paus
- Department of Dermatology Laboratory for Neuroendocrinology of the Skin and Interdisciplinary Endocrinology University of Münster Von Esmarch‐Str. 58 48149 Münster Germany
- Centre for Dermatology Research Institute of Inflammation and Repair University of Manchester Manchester U.K
| | - T.A. Luger
- Department of Dermatology Laboratory for Neuroendocrinology of the Skin and Interdisciplinary Endocrinology University of Münster Von Esmarch‐Str. 58 48149 Münster Germany
| | - M. Böhm
- Department of Dermatology Laboratory for Neuroendocrinology of the Skin and Interdisciplinary Endocrinology University of Münster Von Esmarch‐Str. 58 48149 Münster Germany
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Novel non-angiogenic role for mesenchymal stem cell-derived vascular endothelial growth factor on keratinocytes during wound healing. Cytokine Growth Factor Rev 2018; 44:69-79. [PMID: 30470511 DOI: 10.1016/j.cytogfr.2018.11.002] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 11/12/2018] [Indexed: 12/21/2022]
Abstract
With chronic wounds remaining a substantial healthcare issue, new therapies are sought to improve patient outcomes. Various studies have explored the benefits of promoting angiogenesis in wounds by targeting proangiogenic factors such as Vascular Endothelial Growth Factor (VEGF) family members to improve wound healing. Along similar lines, Mesenchymal Stem Cell (MSC) secretions, usually containing VEGF, have been used to improve angiogenesis in wound healing via a paracrine mechanism. Recent evidence for keratinocyte VEGF receptor expression, as well as proliferative and chemotactic responses by keratinocytes to exogenous VEGFA in vitro implies distinct non-angiogenic actions for VEGF during wound healing. In this review, we discuss the expression of VEGF family members and their receptors in keratinocytes in relation to the potential for wound healing treatments. We also explore recent findings of MSC secreted paracrine wound healing activity on keratinocytes. We report here the concept of keratinocyte wound healing responses driven by MSC-derived VEGF that is supported in the literature, providing a new mechanism for cell-free therapy of chronic wounds.
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Wolf DA, Beeson W, Rachel JD, Keller GS, Hanke CW, Waibel J, Leavitt M, Sacopulos M. Mesothelial Stem Cells and Stromal Vascular Fraction for Skin Rejuvenation. Facial Plast Surg Clin North Am 2018; 26:513-532. [PMID: 30213431 DOI: 10.1016/j.fsc.2018.06.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The use of stem cells in regenerative medicine and specifically facial rejuvenation is thought provoking and controversial. Today there is increased emphasis on tissue engineering and regenerative medicine, which translates into a need for a reliable source of stem cells in addition to biomaterial scaffolds and cytokine growth factors. Adipose tissue is currently recognized as an accessible and abundant source for adult stem cells. Cellular therapies and tissue engineering are still in their infancy, and additional basic science and preclinical studies are needed before cosmetic and reconstructive surgical applications can be routinely undertaken and satisfactory levels of patient safety achieved.
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Affiliation(s)
- David A Wolf
- Johnson Space Center, Houston, TX, USA; EarthTomorrow, Inc, 1714 Neptune Lane, Houston, TX 77062, USA; Purdue University, West Lafayette, IN, USA
| | - William Beeson
- Facial Plastics, Indianapolis, IN, USA; Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
| | | | - Gregory S Keller
- Facial Plastics, Santa Barbara, CA, USA; Facial Plastics, Los Angeles, CA, USA
| | - C William Hanke
- Dermatology, Indianapolis, IN, USA; Laser and Skin Center of Indiana, 13400 North Meridian Street, Suite 290, Carmel, IN 46032, USA; ACGME Micrographic Surgery, Dermatologic Oncology Fellowship Training Program, St. Vincent Hospital, Indianapolis, IN, USA; University of Iowa-Carver College of Medicine, Iowa City, IA, USA; University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Jill Waibel
- Dermatology, Miami Dermatology and Laser Institute, 7800 Southwest 87th Avenue, Suite B200, Miami, FL 33173, USA; Baptist Hospital of Miami, Miami, FL, USA; Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Matt Leavitt
- Dermatology, Orlando, FL, USA; Advanced Dermatology and Cosmetic Surgery, The Hair Foundation, 260 Lookout Place Suite 103, Maitland, FL 32751, USA; University of Central Florida, 6850 Lake Nona Boulevard, Orlando, FL 32827, USA; Nova Southeastern University, 4850 Millenium Boulevard, Orlando, FL 32839, USA
| | - Michael Sacopulos
- Medical Risk Management, Medical Risk Institute, 676 Ohio Street, Terre Haute, IN 47807, USA
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Wu Q, Lei X, Chen L, Zheng Y, Huang H, Qian C, Liang Z. Autologous platelet-rich gel combined with in vitro amplification of bone marrow mesenchymal stem cell transplantation to treat the diabetic foot ulcer: a case report. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:307. [PMID: 30211195 DOI: 10.21037/atm.2018.07.12] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The diabetic foot ulcer (DFU) is the leading cause of the high mortality and morbidity rates of diabetes patients, and the DFU accounts for approximately 15% of all diagnosed diabetes cases in China. Traditional treatment is typically ineffective for DFUs. Here, we present a case of DFU that was successfully treated with an autologous platelet-rich gel (APG) and in vitro amplification of bone marrow mesenchymal stem cell (BMMSC) transplantation. A 54-year-old woman initially presented with a right foot diabetic ulcer at the hospital. A wound at the lateral malleolus of the right foot was observed with exudation and infection. The standard treatment included glucose reduction with insulin, blood lipid control with atorvastatin, circulation improvement with alprostadil, anti-infection treatment with sensitive antibiotics, debridement, dressing, and continuous negative pressure suction, and after the standard treatment, the APG combined with in vitro amplification of BMMSC transplantation was used to help the healing of the ulcer. All of the above interventions may have contributed to the healing of the ulcer, and an APG combined with in vitro amplification of BMMSCs may promote DFU healing. The difficulty of DFU treatment remains a challenge, particularly in diabetic patients who develop foot ulcers, due to the complexity of its multifaceted pathogenesis. This case represents an effective adjuvant treatment for such patients.
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Affiliation(s)
- Qinan Wu
- Endocrine Department, the First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Xiaotian Lei
- Endocrine Department, the First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Liu Chen
- Endocrine Department, the First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Yanling Zheng
- Endocrine Department, the First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Hongmei Huang
- Blood Transfusion Department, the First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Cheng Qian
- Biotherapy Center, the First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Ziwen Liang
- Endocrine Department, the First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing 400038, China
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Lopes L, Setia O, Aurshina A, Liu S, Hu H, Isaji T, Liu H, Wang T, Ono S, Guo X, Yatsula B, Guo J, Gu Y, Navarro T, Dardik A. Stem cell therapy for diabetic foot ulcers: a review of preclinical and clinical research. Stem Cell Res Ther 2018; 9:188. [PMID: 29996912 PMCID: PMC6042254 DOI: 10.1186/s13287-018-0938-6] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 06/15/2018] [Accepted: 06/20/2018] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Diabetic foot ulcer (DFU) is a severe complication of diabetes, preceding most diabetes-related amputations. DFUs require over US$9 billion for yearly treatment and are now a global public health issue. DFU occurs in the setting of ischemia, infection, neuropathy, and metabolic disorders that result in poor wound healing and poor treatment options. Recently, stem cell therapy has emerged as a new interventional strategy to treat DFU and appears to be safe and effective in both preclinical and clinical trials. However, variability in the stem cell type and origin, route and protocol for administration, and concomitant use of angioplasty confound easy interpretation and generalization of the results. METHODS The PubMed, Google Scholar, and EMBASE databases were searched and 89 preclinical and clinical studies were selected for analysis. RESULTS There was divergence between preclinical and clinical studies regarding stem cell type, origin, and delivery techniques. There was heterogeneous preclinical and clinical study design and few randomized clinical trials. Granulocyte-colony stimulating factor was employed in some studies but with differing protocols. Concomitant performance of angioplasty with stem cell therapy showed increased efficiency compared to either therapy alone. CONCLUSIONS Stem cell therapy is an effective treatment for diabetic foot ulcers and is currently used as an alternative to amputation for some patients without other options for revascularization. Concordance between preclinical and clinical studies may help design future randomized clinical trials.
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Affiliation(s)
- Lara Lopes
- Vascular Biology and Therapeutics Program and Department of Surgery , Yale School of Medicine, Yale University, New Haven, CT USA
- Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Ocean Setia
- Vascular Biology and Therapeutics Program and Department of Surgery , Yale School of Medicine, Yale University, New Haven, CT USA
| | - Afsha Aurshina
- Vascular Biology and Therapeutics Program and Department of Surgery , Yale School of Medicine, Yale University, New Haven, CT USA
| | - Shirley Liu
- Vascular Biology and Therapeutics Program and Department of Surgery , Yale School of Medicine, Yale University, New Haven, CT USA
| | - Haidi Hu
- Vascular Biology and Therapeutics Program and Department of Surgery , Yale School of Medicine, Yale University, New Haven, CT USA
| | - Toshihiko Isaji
- Vascular Biology and Therapeutics Program and Department of Surgery , Yale School of Medicine, Yale University, New Haven, CT USA
| | - Haiyang Liu
- Vascular Biology and Therapeutics Program and Department of Surgery , Yale School of Medicine, Yale University, New Haven, CT USA
| | - Tun Wang
- Vascular Biology and Therapeutics Program and Department of Surgery , Yale School of Medicine, Yale University, New Haven, CT USA
| | - Shun Ono
- Vascular Biology and Therapeutics Program and Department of Surgery , Yale School of Medicine, Yale University, New Haven, CT USA
| | - Xiangjiang Guo
- Vascular Biology and Therapeutics Program and Department of Surgery , Yale School of Medicine, Yale University, New Haven, CT USA
| | - Bogdan Yatsula
- Vascular Biology and Therapeutics Program and Department of Surgery , Yale School of Medicine, Yale University, New Haven, CT USA
| | - Jianming Guo
- Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Yongquan Gu
- Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Tulio Navarro
- Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Alan Dardik
- Vascular Biology and Therapeutics Program and Department of Surgery , Yale School of Medicine, Yale University, New Haven, CT USA
- VA Connecticut Healthcare System, West Haven, CT USA
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Karamanou K, Perrot G, Maquart FX, Brézillon S. Lumican as a multivalent effector in wound healing. Adv Drug Deliv Rev 2018; 129:344-351. [PMID: 29501701 DOI: 10.1016/j.addr.2018.02.011] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 01/31/2018] [Accepted: 02/26/2018] [Indexed: 12/14/2022]
Abstract
Wound healing, a complex physiological process, is responsible for tissue repair after exposure to destructive stimuli, without resulting in complete functional regeneration. Injuries can be stromal or epithelial, and most cases of wound repair have been studied in the skin and cornea. Lumican, a small leucine-rich proteoglycan, is expressed in the extracellular matrices of several tissues, such as the cornea, cartilage, and skin. This molecule has been shown to regulate collagen fibrillogenesis, keratinocyte phenotypes, and corneal transparency modulation. Lumican is also involved in the extravasation of inflammatory cells and angiogenesis, which are both critical in stromal wound healing. Lumican is the only member of the small leucine-rich proteoglycan family expressed by the epithelia during wound healing. This review summarizes the importance of lumican in wound healing and potential methods of lumican drug delivery to target wound repair are discussed. The involvement of lumican in corneal wound healing is described based on in vitro and in vivo models, with critical emphasis on its underlying mechanisms of action. Similarly, the expression and role of lumican in the healing of other tissues are presented, with emphasis on skin wound healing. Overall, lumican promotes normal wound repair and broadens new therapeutic perspectives for impaired wound healing.
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Affiliation(s)
- Konstantina Karamanou
- Université de Reims Champagne-Ardenne, Laboratoire de Biochimie Médicale et Biologie Moléculaire, Reims, France; Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece; CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, Reims, France
| | - Gwenn Perrot
- Université de Reims Champagne-Ardenne, Laboratoire de Biochimie Médicale et Biologie Moléculaire, Reims, France; CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, Reims, France
| | - Francois-Xavier Maquart
- Université de Reims Champagne-Ardenne, Laboratoire de Biochimie Médicale et Biologie Moléculaire, Reims, France; CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, Reims, France; CHU Reims, Laboratoire Central de Biochimie, Reims, France
| | - Stéphane Brézillon
- Université de Reims Champagne-Ardenne, Laboratoire de Biochimie Médicale et Biologie Moléculaire, Reims, France; CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, Reims, France.
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Mahmoudian-Sani MR, Rafeei F, Amini R, Saidijam M. The effect of mesenchymal stem cells combined with platelet-rich plasma on skin wound healing. J Cosmet Dermatol 2018; 17:650-659. [PMID: 29504236 DOI: 10.1111/jocd.12512] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/15/2018] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Mesenchymal stem cells (MSCs) are multipotent stem cells that have the potential of proliferation, high self-renewal, and the potential of multilineage differentiation. The differentiation potential of the MSCs in vivo and in vitro has caused these cells to be regarded as potentially appropriate tools for wound healing. After the burn, trauma or removal of the tumor of wide wounds is developed. Although standard treatment for skin wounds is primary healing or skin grafting, they are not always practical mainly because of limited autologous skin grafting. EVIDENCE ACQUISITIONS Directory of Open Access Journals (DOAJ), Google Scholar, PubMed (NLM), LISTA (EBSCO), and Web of Science have been searched. EVIDENCE SYNTHESIS For clinical use of the MSCs in wound healing, two key issues should be taken into account: First, engineering biocompatible scaffolds clinical use of which leads to the least amount of side effects without any immunologic response and secondly, use of stem cells secretions with the least amount of clinical complications despite their high capability of healing damage. CONCLUSION In light of the MSCs' high capability of proliferation and multilineage differentiation as well as their significant role in modulating immunity, these cells can be used in combination with tissue engineering techniques. Moreover, the MSCs' secretions can be used in cell therapy to heal many types of wounds. The combination of MSCs and PRP aids wound healing which could potentially be used to promote wound healing.
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Affiliation(s)
| | - Fatemeh Rafeei
- Student Research Committee, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Razieh Amini
- Department of Genetics and Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Massoud Saidijam
- Department of Genetics and Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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Yu COL, Leung KS, Jiang JL, Wang TBY, Chow SKH, Cheung WH. Low-Magnitude High-Frequency Vibration Accelerated the Foot Wound Healing of n5-streptozotocin-induced Diabetic Rats by Enhancing Glucose Transporter 4 and Blood Microcirculation. Sci Rep 2017; 7:11631. [PMID: 28912573 PMCID: PMC5599683 DOI: 10.1038/s41598-017-11934-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Accepted: 08/30/2017] [Indexed: 01/13/2023] Open
Abstract
Delayed wound healing is a Type 2 diabetes mellitus (DM) complication caused by hyperglycemia, systemic inflammation, and decreased blood microcirculation. Skeletal muscles are also affected by hyperglycemia, resulting in reduced blood flow and glucose uptake. Low Magnitude High Frequency Vibration (LMHFV) has been proven to be beneficial to muscle contractility and blood microcirculation. We hypothesized that LMHFV could accelerate the wound healing of n5-streptozotocin (n5-STZ)-induced DM rats by enhancing muscle activity and blood microcirculation. This study investigated the effects of LMHFV in an open foot wound created on the footpad of n5-STZ-induced DM rats (DM_V), compared with no-treatment DM (DM), non-DM vibration (Ctrl_V) and non-DM control rats (Ctrl) on Days 1, 4, 8 and 13. Results showed that the foot wounds of DM_V and Ctrl_V rats were significantly reduced in size compared to DM and Ctrl rats, respectively, at Day 13. The blood glucose level of DM_V rats was significantly reduced, while the glucose transporter 4 (GLUT4) expression and blood microcirculation of DM_V rats were significantly enhanced in comparison to those of DM rats. In conclusion, LMHFV can accelerate the foot wound healing process of n5-STZ rats.
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Affiliation(s)
- Caroline Oi-Ling Yu
- Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Kwok-Sui Leung
- Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jonney Lei Jiang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Tina Bai-Yan Wang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Simon Kwoon-Ho Chow
- Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.,The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, PR China
| | - Wing-Hoi Cheung
- Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China. .,The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, PR China.
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Yu COL, Leung KS, Fung KP, Lam FFY, Ng ESK, Lau KM, Chow SKH, Cheung WH. The characterization of a full-thickness excision open foot wound model in n5-streptozotocin (STZ)-induced type 2 diabetic rats that mimics diabetic foot ulcer in terms of reduced blood circulation, higher C-reactive protein, elevated inflammation, and reduced cell proliferation. Exp Anim 2017; 66:259-269. [PMID: 28413186 PMCID: PMC5543247 DOI: 10.1538/expanim.17-0016] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Delayed foot wound healing is a major complication attributed to hyperglycemia in type 2
diabetes mellitus (DM) patients, and these wounds may develop into foot ulcers. There are
at least two types of DM wound models used in rodents to study delayed wound healing.
However, clinically relevant animal models are not common. Most models use type 1 DM
rodents or wounds created on the back rather than on the foot. An open full-thickness
excision wound on the footpad of type 2 DM rats is more clinically relevant, but such a
model has not yet been characterized systematically. The objective of this study was to
investigate and characterize how DM affected a full-thickness excision open foot wound in
n5-streptozotocin (n5-STZ)-induced type 2 DM rats. We hypothesized that elevated
inflammation, reduced blood circulation, and cell proliferation due to hyperglycemia could
delay the wound healing of DM rats. The wounds of DM rats were compared with those of
non-DM rats (Ctrl) at Days 1 and 8 post wounding. The wound healing process of the DM rats
was significantly delayed compared with that of the Ctrl rats. The DM rats also had higher
C-reactive protein (CRP) and lower blood circulation and proliferating cell nuclear
antigen (PCNA) in DM wounds. This confirmed that elevated inflammation and reduced blood
flow and cell proliferation delayed foot wound healing in the n5-STZ rats. Hence, this
open foot wound animal model provides a good approach to study the process of delayed
wound healing.
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Affiliation(s)
- Caroline Oi-Ling Yu
- Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, Hong Kong, P.R. China
| | - Kwok-Sui Leung
- Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, Hong Kong, P.R. China
| | - Kwok-Pui Fung
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, P.R. China
| | - Francis Fu-Yuen Lam
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, P.R. China
| | - Ethel Sau-Kuen Ng
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, P.R. China
| | - Kit-Man Lau
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, P.R. China.,State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, Hong Kong, P.R. China
| | - Simon Kwoon-Ho Chow
- Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, Hong Kong, P.R. China.,The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, The Chinese University of Hong Kong Shenzhen Research Institute, 10 Yue Xin Er Dao, Shenzhen, P.R. China
| | - Wing-Hoi Cheung
- Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, Hong Kong, P.R. China.,The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, The Chinese University of Hong Kong Shenzhen Research Institute, 10 Yue Xin Er Dao, Shenzhen, P.R. China
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Zorzopulos J, Opal SM, Hernando-Insúa A, Rodriguez JM, Elías F, Fló J, López RA, Chasseing NA, Lux-Lantos VA, Coronel MF, Franco R, Montaner AD, Horn DL. Immunomodulatory oligonucleotide IMT504: Effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy. World J Stem Cells 2017; 9:45-67. [PMID: 28396715 PMCID: PMC5368622 DOI: 10.4252/wjsc.v9.i3.45] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 10/12/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
The immune responses of humans and animals to insults (i.e., infections, traumas, tumoral transformation and radiation) are based on an intricate network of cells and chemical messengers. Abnormally high inflammation immediately after insult or abnormally prolonged pro-inflammatory stimuli bringing about chronic inflammation can lead to life-threatening or severely debilitating diseases. Mesenchymal stem cell (MSC) transplant has proved to be an effective therapy in preclinical studies which evaluated a vast diversity of inflammatory conditions. MSCs lead to resolution of inflammation, preparation for regeneration and actual regeneration, and then ultimate return to normal baseline or homeostasis. However, in clinical trials of transplanted MSCs, the expectations of great medical benefit have not yet been fulfilled. As a practical alternative to MSC transplant, a synthetic drug with the capacity to boost endogenous MSC expansion and/or activation may also be effective. Regarding this, IMT504, the prototype of a major class of immunomodulatory oligonucleotides, induces in vivo expansion of MSCs, resulting in a marked improvement in preclinical models of neuropathic pain, osteoporosis, diabetes and sepsis. IMT504 is easily manufactured and has an excellent preclinical safety record. In the small number of patients studied thus far, IMT504 has been well-tolerated, even at very high dosage. Further clinical investigation is necessary to demonstrate the utility of IMT504 for resolution of inflammation and regeneration in a broad array of human diseases that would likely benefit from an immunoprotective/immunoregenerative therapy.
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45
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The Roles of Insulin-Like Growth Factors in Mesenchymal Stem Cell Niche. Stem Cells Int 2017; 2017:9453108. [PMID: 28298931 PMCID: PMC5337393 DOI: 10.1155/2017/9453108] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 12/22/2016] [Accepted: 01/18/2017] [Indexed: 12/12/2022] Open
Abstract
Many tissues contain adult mesenchymal stem cells (MSCs), which may be used in tissue regeneration therapies. However, the MSC availability in most tissues is limited which demands expansion in vitro following isolation. Like many developing cells, the state of MSCs is affected by the surrounding microenvironment, and mimicking this natural microenvironment that supports multipotent or differentiated state in vivo is essential to understand for the successful use of MSC in regenerative therapies. Many researchers are, therefore, optimizing cell culture conditions in vitro by altering growth factors, extracellular matrices, chemicals, oxygen tension, and surrounding pH to enhance stem cells self-renewal or differentiation. Insulin-like growth factors (IGFs) system has been demonstrated to play an important role in stem cell biology to either promote proliferation and self-renewal or enhance differentiation onset and outcome, depending on the cell culture conditions. In this review, we will describe the importance of IGFs, IGF-1 and IGF-2, in development and in the MSC niche and how they affect the pluripotency or differentiation towards multiple lineages of the three germ layers.
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46
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Mesenchymal Stem Cells from Adipose Tissue in Clinical Applications for Dermatological Indications and Skin Aging. Int J Mol Sci 2017; 18:ijms18010208. [PMID: 28117680 PMCID: PMC5297838 DOI: 10.3390/ijms18010208] [Citation(s) in RCA: 119] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 01/05/2017] [Accepted: 01/05/2017] [Indexed: 12/13/2022] Open
Abstract
Operating at multiple levels of control, mesenchymal stem cells from adipose tissue (ADSCs) communicate with organ systems to adjust immune response, provide signals for differentiation, migration, enzymatic reactions, and to equilibrate the regenerative demands of balanced tissue homeostasis. The identification of the mechanisms by which ADSCs accomplish these functions for dermatological rejuvenation and wound healing has great potential to identify novel targets for the treatment of disorders and combat aging. Herein, we review new insights into the role of adipose-derived stem cells in the maintenance of dermal and epidermal homeostasis, and recent advances in clinical applications of ADSCs related to dermatology.
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47
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Cao Y, Gang X, Sun C, Wang G. Mesenchymal Stem Cells Improve Healing of Diabetic Foot Ulcer. J Diabetes Res 2017; 2017:9328347. [PMID: 28386568 PMCID: PMC5366201 DOI: 10.1155/2017/9328347] [Citation(s) in RCA: 109] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 02/28/2017] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem cells (MSCs), an ideal cell source for regenerative therapy with no ethical issues, play an important role in diabetic foot ulcer (DFU). Growing evidence has demonstrated that MSCs transplantation can accelerate wound closure, ameliorate clinical parameters, and avoid amputation. In this review, we clarify the mechanism of preclinical studies, as well as safety and efficacy of clinical trials in the treatment of DFU. Bone marrow-derived mesenchymal stem cells (BM-MSCs), compared with MSCs derived from other tissues, may be a suitable cell type that can provide easy, effective, and cost-efficient transplantation to treat DFU and protect patients from amputation.
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Affiliation(s)
- Yue Cao
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun 130021, China
| | - Xiaokun Gang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun 130021, China
| | - Chenglin Sun
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun 130021, China
| | - Guixia Wang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun 130021, China
- *Guixia Wang:
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48
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Wu Q, Chen B, Liang Z. Mesenchymal Stem Cells as a Prospective Therapy for the Diabetic Foot. Stem Cells Int 2016; 2016:4612167. [PMID: 27867398 PMCID: PMC5102750 DOI: 10.1155/2016/4612167] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 09/28/2016] [Accepted: 10/10/2016] [Indexed: 12/14/2022] Open
Abstract
The diabetic foot is a serious complication of diabetes. Mesenchymal stem cells are an abundant source of stem cells which occupy a special position in cell therapies, and recent studies have suggested that mesenchymal stem cells can play essential roles in treatments for the diabetic foot. Here, we discuss the advances that have been made in mesenchymal stem cell treatments for this condition. The roles and functional mechanisms of mesenchymal stem cells in the diabetic foot are also summarized, and insights into current and future studies are presented.
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Affiliation(s)
- Qinan Wu
- Department of Endocrinology, The First Affiliated Hospital of The Third Military Medical University, Chongqing 400038, China
| | - Bing Chen
- Department of Endocrinology, The First Affiliated Hospital of The Third Military Medical University, Chongqing 400038, China
| | - Ziwen Liang
- Department of Endocrinology, The First Affiliated Hospital of The Third Military Medical University, Chongqing 400038, China
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Abstract
Diabetic polyneuropathy (DPN) is the most common complication that emerges early in patients who have diabetes. Curative treatment for overt or symptomatic DPN has not been established, requiring much effort to explore new modalities. Thus, the use of various kinds of stem cells as a potential therapeutic option for DPN is of particular interest. The beneficial effects were proposed to be attributed to either cytokine released from transplanted stem cells or the differentiation of stem cells to substitute the damaged peripheral nerve. Furthermore, based on the concept that humoral factors secreted from stem cells play a pivotal role in tissue regeneration, the utilization of conditioned medium derived from the stem cell culture serves as a novel tool for regenerative therapy. However, many questions have not been yet answered to determine whether stem cell therapy is essential in clinical application of DPN. In this report, we review the current status of preclinical studies on stem cell therapy for DPN and discuss future prospects.
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Affiliation(s)
- Hiroki Mizukami
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.
| | - Soroku Yagihashi
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
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50
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Lau HC, Kim A. Pharmaceutical perspectives of impaired wound healing in diabetic foot ulcer. JOURNAL OF PHARMACEUTICAL INVESTIGATION 2016. [DOI: 10.1007/s40005-016-0268-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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