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Ahmed MM, Malachowska B, Guha C. Radiation-Induced Tissue Regeneration: Pathways, Mechanisms, and Therapeutic Potential. Hematol Oncol Clin North Am 2025; 39:431-452. [PMID: 39827040 DOI: 10.1016/j.hoc.2024.12.003] [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] [Indexed: 01/22/2025]
Abstract
This article explores the paradoxic nature of radiation as both a destructive and regenerative force. The article examines the interplay of signaling pathways, immune modulation, and stem cells in tissue regeneration post radiation, emphasizing the roles of key pathways like Wnt, Hedgehog, Notch, and p53. It highlights advancements in low-dose radiation therapy, extracellular vesicles, and stem cell-based interventions. Furthermore, the immune system's dual role in repair and damage is dissected, along with technologies such as artificial intelligence and bioengineered scaffolds that enhance therapeutic outcomes. The article offers a roadmap for integrating therapeutic innovation with regenerative medicine to improve patient outcomes.
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Affiliation(s)
- Mansoor M Ahmed
- Division of Radiation Biology and Molecular Therapeutics, Department of Radiation Oncology, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Beata Malachowska
- Department of Radiation Oncology, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Chandan Guha
- Department of Radiation Oncology, Institute for Onco-Physics, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY 10461, USA.
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Seon JK, Kuppa SS, Kang JY, Lee JS, Park SA, Yoon TR, Park KS, Kim HK. Peptide derived from stromal cell-derived factor 1δ enhances the in vitro expression of osteogenic proteins via bone marrow stromal cell differentiation and promotes bone formation in in vivo models. Biomater Sci 2023; 11:6587-6599. [PMID: 37605799 DOI: 10.1039/d3bm00798g] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2023]
Abstract
Mesenchymal stem cells (MSCs) rely on chemokines and chemokine receptors to execute their biological and physiological functions. Stromal cell-derived factor-1 (SDF-1) is upregulated in injury sites, where it acts as a chemotactic agent, attracting CXCR4-expressing MSCs, which play a pivotal role in the healing and regeneration of tissue throughout the body. Furthermore, SDF-1 expression has been observed in regions experiencing inflammation-induced bone destruction and fracture sites. In this study, we identified a novel peptide called bone-forming peptide-5 (BFP-5), derived from SDF-1δ, which can promote the osteogenesis of MSCs as well as bone formation and healing. Multipotent bone marrow stromal cells treated with BFP-5 showed enhanced alizarin red S staining and higher alkaline phosphatase (ALP) activity. Moreover, ALP and osterix proteins were more abundantly expressed when cells were treated with BFP-5 than SDF-1α. Histology and microcomputed tomography data at 12 weeks demonstrated that both rabbit and goat models transplanted with polycaprolactone (PCL) scaffolds coated with BFP-5 showed significantly greater bone formation than animals transplanted with PCL scaffolds alone. These findings suggest that BFP-5 could be useful in the development of related therapies for conditions associated with bones.
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Affiliation(s)
- Jong Keun Seon
- Department of Biomedical Sciences, Chonnam National University Medical School, Chonnam National University Hwasun Hospital, 322 Seoyang-ro, Hwasun-eup, Jeonnam, 58128, Korea
- Department of Orthopaedics Surgery, Center for Joint Disease of Chonnam National University Hwasun Hospital, 322 Seoyang-ro, Hwasun-eup, Jeonnam, 519-763, Korea.
- Korea Biomedical Materials and Devices Innovation Research Center of Chonnam National University Hospital, 42, Jebong-ro, Dong-gu, Gwangju, 501-757, Korea
| | - Sree Samanvitha Kuppa
- Department of Biomedical Sciences, Chonnam National University Medical School, Chonnam National University Hwasun Hospital, 322 Seoyang-ro, Hwasun-eup, Jeonnam, 58128, Korea
- Department of Orthopaedics Surgery, Center for Joint Disease of Chonnam National University Hwasun Hospital, 322 Seoyang-ro, Hwasun-eup, Jeonnam, 519-763, Korea.
- Korea Biomedical Materials and Devices Innovation Research Center of Chonnam National University Hospital, 42, Jebong-ro, Dong-gu, Gwangju, 501-757, Korea
| | - Ju Yeon Kang
- Department of Orthopaedics Surgery, Center for Joint Disease of Chonnam National University Hwasun Hospital, 322 Seoyang-ro, Hwasun-eup, Jeonnam, 519-763, Korea.
- Korea Biomedical Materials and Devices Innovation Research Center of Chonnam National University Hospital, 42, Jebong-ro, Dong-gu, Gwangju, 501-757, Korea
| | - Jun Sik Lee
- Department of Biology, Integrative Biological Sciences & BK21 FOUR educational Research Group for Age-Associated Disorder Control Technology, Immunology Research Lab, College of Natural Sciences, Chosun University, Dong-gu, Gwangju 501-759, Korea
| | - Su A Park
- Nano Convergence & Manufacturing Systems, Korea Institute of Machinery and Materials (KIMM), Daejon 34103, Korea
| | - Taek Rim Yoon
- Department of Orthopaedics Surgery, Center for Joint Disease of Chonnam National University Hwasun Hospital, 322 Seoyang-ro, Hwasun-eup, Jeonnam, 519-763, Korea.
| | - Kyung Soon Park
- Department of Orthopaedics Surgery, Center for Joint Disease of Chonnam National University Hwasun Hospital, 322 Seoyang-ro, Hwasun-eup, Jeonnam, 519-763, Korea.
| | - Hyung Keun Kim
- Department of Orthopaedics Surgery, Center for Joint Disease of Chonnam National University Hwasun Hospital, 322 Seoyang-ro, Hwasun-eup, Jeonnam, 519-763, Korea.
- Korea Biomedical Materials and Devices Innovation Research Center of Chonnam National University Hospital, 42, Jebong-ro, Dong-gu, Gwangju, 501-757, Korea
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Kobayashi Y, Kida Y, Kabuto Y, Morihara T, Sukenari T, Nakagawa H, Onishi O, Oda R, Kida N, Tanida T, Matsuda KI, Tanaka M, Takahashi K. Healing Effect of Subcutaneous Administration of Granulocyte Colony-Stimulating Factor on Acute Rotator Cuff Injury in a Rat Model. Tissue Eng Part A 2021; 27:1205-1212. [PMID: 34432525 DOI: 10.1089/ten.tea.2020.0239.a] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Granulocyte colony-stimulating factor (G-CSF) is a cytokine that mobilizes bone marrow-derived cells (BMDCs) to peripheral blood and has been clinically used to treat neutropenia. Previously, we reported that BMDCs migrated into the rotator cuff repair site via peripheral blood in the healing process. However, techniques to accelerate the healing process using the peripheral blood pathway have not been established. We evaluated whether G-CSF has a noteworthy effect on improving rotator cuff healing by enhancing the influx of BMDCs into the peripheral blood. We used Sprague-Dawley rats and chimeric rats, selectively expressing green fluorescent protein (GFP) in BMDCs. Their bilateral supraspinatus tendons were resected and sutured to the greater tuberosity of the humerus using the Masson-Allen technique, and G-CSF was subcutaneously injected for 5 days after surgery. Several GFP-positive cells were observed around the enthesis in the G-CSF-treated group compared with that in the Control group. Histological analysis revealed that the tendon-to-bone maturing scores and the Safranin O-stained cartilaginous areas were significantly higher in G-CSF-injected rats than in the control rats at weeks 4 and 8 after surgery. Consistently, the ultimate force to failure in the G-CSF-treated group significantly increased compared with the Control group at weeks 4 and 8 after surgery. These results suggest that BMDCs mobilized into the peripheral blood after G-CSF administration migrated to the rotator cuff repair area and effectively enhanced rotator cuff healing by promoting tenocyte and cartilage matrix production. In conclusion, the BMDC mobilization technique by G-CSF treatment via peripheral blood will provide a potential therapeutic approach for rotator cuff healing with clinically relevant applications. Impact statement As the retear rate following rotator cuff repair is high, new methods to aid its healing are required. Granulocyte colony-stimulating factor (G-CSF) has been used clinically and may represent a novel approach to treating rotator cuff tear. Herein, using a rat model, we elucidate the kinetics of bone marrow-derived mesenchymal stem cells at the repair site following G-CSF administration and describe the underlying mechanism by which G-CSF can help promote the repair of the rotator cuff.
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Affiliation(s)
- Yusuke Kobayashi
- Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshikazu Kida
- Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yukichi Kabuto
- Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Toru Morihara
- Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tsuyoshi Sukenari
- Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Haruhiko Nakagawa
- Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Okihiro Onishi
- Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Ryo Oda
- Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Noriyuki Kida
- Faculty of Arts and Sciences, Kyoto Institute of Technology, Kyoto, Japan
| | - Takashi Tanida
- Department of Anatomy and Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Ken Ichi Matsuda
- Department of Anatomy and Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Masaki Tanaka
- Department of Anatomy and Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kenji Takahashi
- Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Engineering the Composition of Microfibers to Enhance the Remodeling of a Cell-Free Vascular Graft. NANOMATERIALS 2021; 11:nano11061613. [PMID: 34202961 PMCID: PMC8235366 DOI: 10.3390/nano11061613] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/14/2021] [Accepted: 06/17/2021] [Indexed: 02/06/2023]
Abstract
The remodeling of vascular grafts is critical for blood vessel regeneration. However, most scaffold materials have limited cell infiltration. In this study, we designed and fabricated a scaffold that incorporates a fast-degrading polymer polydioxanone (PDO) into the microfibrous structure by means of electrospinning technology. Blending PDO with base polymer decreases the density of electrospun microfibers yet did not compromise the mechanical and structural properties of the scaffold, and effectively enhanced cell infiltration. We then used this technique to fabricate a tubular scaffold with heparin conjugated to the surface to suppress thrombosis, and the construct was implanted into the carotid artery as a vascular graft in animal studies. This graft significantly promoted cell infiltration, and the biochemical cues such as immobilized stromal cell-derived factor-1α further enhanced cell recruitment and the long-term patency of the grafts. This work provides an approach to optimize the microfeatures of vascular grafts, and will have broad applications in scaffold design and fabrication for regenerative engineering.
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5
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Shoushrah SH, Transfeld JL, Tonk CH, Büchner D, Witzleben S, Sieber MA, Schulze M, Tobiasch E. Sinking Our Teeth in Getting Dental Stem Cells to Clinics for Bone Regeneration. Int J Mol Sci 2021; 22:6387. [PMID: 34203719 PMCID: PMC8232184 DOI: 10.3390/ijms22126387] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/27/2021] [Accepted: 06/02/2021] [Indexed: 12/12/2022] Open
Abstract
Dental stem cells have been isolated from the medical waste of various dental tissues. They have been characterized by numerous markers, which are evaluated herein and differentiated into multiple cell types. They can also be used to generate cell lines and iPSCs for long-term in vitro research. Methods for utilizing these stem cells including cellular systems such as organoids or cell sheets, cell-free systems such as exosomes, and scaffold-based approaches with and without drug release concepts are reported in this review and presented with new pictures for clarification. These in vitro applications can be deployed in disease modeling and subsequent pharmaceutical research and also pave the way for tissue regeneration. The main focus herein is on the potential of dental stem cells for hard tissue regeneration, especially bone, by evaluating their potential for osteogenesis and angiogenesis, and the regulation of these two processes by growth factors and environmental stimulators. Current in vitro and in vivo publications show numerous benefits of using dental stem cells for research purposes and hard tissue regeneration. However, only a few clinical trials currently exist. The goal of this review is to pinpoint this imbalance and encourage scientists to pick up this research and proceed one step further to translation.
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Affiliation(s)
| | | | | | | | | | | | | | - Edda Tobiasch
- Department of Natural Sciences, Bonn-Rhein-Sieg University of Applied Sciences, von-Liebig- Strasse. 20, 53359 Rheinbach, Germany; (S.H.S.); (J.L.T.); (C.H.T.); (D.B.); (S.W.); (M.A.S.); (M.S.)
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Ibrutinib Has Time-dependent On- and Off-target Effects on Plasma Biomarkers and Immune Cells in Chronic Lymphocytic Leukemia. Hemasphere 2021; 5:e564. [PMID: 33912812 PMCID: PMC8078281 DOI: 10.1097/hs9.0000000000000564] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 03/22/2021] [Indexed: 02/07/2023] Open
Abstract
Supplemental Digital Content is available in the text. Ibrutinib is a covalently binding inhibitor of the B-cell receptor signaling-mediator Bruton’s tyrosine kinase (BTK) with great efficacy in chronic lymphocytic leukemia (CLL). Common side effects like atrial fibrillation (AF), bleeding and infections might be caused by ibrutinib’s inhibition of other kinases in non-B cells. Five-year follow-up of plasma biomarkers by proximity extension assay and immune cell numbers by flow cytometry during ibrutinib treatment revealed that 86 of the 265 investigated plasma biomarkers significantly changed during treatment, 74 of which decreased. Among the 12 markers that increased, 6 are associated with cardiovascular diseases and therefore potentially involved in ibrutinib-induced AF. Comparison between healthy donors and X-linked agammaglobulinemia (XLA) patients, who have nonfunctional BTK and essentially lack B cells, showed indicative changes in 53 of the 265 biomarkers while none differed significantly. Hence, neither B cells nor BTK-dependent pathways in other cells seem to influence the levels of the studied plasma biomarkers in healthy donors. Regarding immune cells, the absolute number of T cells, including subsets, decreased, paralleling the decreasing tumor burden. T helper 1 (Th1) cell numbers dropped strongly, while Th2 cells remained relatively stable, causing Th2-skewing. Thus, long-term ibrutinib treatment has a profound impact on the plasma proteome and immune cells in patients with CLL.
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Patel S, Das A, Meshram P, Sharma A, Chowdhury A, Jariyal H, Datta A, Sarmah D, Nalla LV, Sahu B, Khairnar A, Bhattacharya P, Srivastava A, Shard A. Pyruvate kinase M2 in chronic inflammations: a potpourri of crucial protein-protein interactions. Cell Biol Toxicol 2021; 37:653-678. [PMID: 33864549 DOI: 10.1007/s10565-021-09605-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 04/05/2021] [Indexed: 11/26/2022]
Abstract
Chronic inflammation (CI) is a primary contributing factor involved in multiple diseases like cancer, stroke, diabetes, Alzheimer's disease, allergy, asthma, autoimmune diseases, coeliac disease, glomerulonephritis, sepsis, hepatitis, inflammatory bowel disease, reperfusion injury, and transplant rejections. Despite several expansions in our understanding of inflammatory disorders and their mediators, it seems clear that numerous proteins participate in the onset of CI. One crucial protein pyruvate kinase M2 (PKM2) much studied in cancer is also found to be inextricably woven in the onset of several CI's. It has been found that PKM2 plays a significant role in several disorders using a network of proteins that interact in multiple ways. For instance, PKM2 forms a close association with epidermal growth factor receptors (EGFRs) for uncontrolled growth and proliferation of tumor cells. In neurodegeneration, PKM2 interacts with apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) to onset Alzheimer's disease pathogenesis. The cross-talk of protein tyrosine phosphatase 1B (PTP1B) and PKM2 acts as stepping stones for the commencement of diabetes. Perhaps PKM2 stores the potential to unlock the pathophysiology of several diseases. Here we provide an overview of the notoriously convoluted biology of CI's and PKM2. The cross-talk of PKM2 with several proteins involved in stroke, Alzheimer's, cancer, and other diseases has also been discussed. We believe that considering the importance of PKM2 in inflammation-related diseases, new options for treating various disorders with the development of more selective agents targeting PKM2 may appear.
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Affiliation(s)
- Sagarkumar Patel
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India
| | - Anwesha Das
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India
| | - Payal Meshram
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India
| | - Ayushi Sharma
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India
| | - Arnab Chowdhury
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India
| | - Heena Jariyal
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India
| | - Aishika Datta
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India
| | - Deepaneeta Sarmah
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India
| | - Lakshmi Vineela Nalla
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India
| | - Bichismita Sahu
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India
| | - Amit Khairnar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India
| | - Pallab Bhattacharya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India
| | - Akshay Srivastava
- Department of Medical Devices, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India
| | - Amit Shard
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India.
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Fang J, Xu J, Zhang Y, Chen H, Ma Z, Huang Z, Hu J. Stromal cell-derived factor-1 may play pivotal role in distraction-stimulated neovascularization of diabetic foot ulcer. Med Hypotheses 2021; 149:110548. [PMID: 33690002 DOI: 10.1016/j.mehy.2021.110548] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/16/2021] [Accepted: 02/24/2021] [Indexed: 02/05/2023]
Abstract
Diabetic foot ulcer (DFU) has become a major medical, social and economic concern worldwide. It is highly desirable to develop promising new solutions to effectively and appropriately treat DFU. In recent years, investigators have used an innovative technology called proximal tibial cortex transverse distraction (PTCTD) to treat DFU and have achieved satisfactory results in terms of improved wound healing and circumvention of amputation as a consequence of enhanced neovascularization and perfusion of the ulcerated feet after the operation, but the underlying mechanism has not been explored. Previous studies have suggested that in addition to stimulating osteogenesis, bone distraction also facilitates neovascularization, which may be associated with the chemokine stromal cell-derived factor-1 (SDF-1). As an important member of the chemokine family, SDF-1 is primarily responsible for the homing and migration of endothelial progenitor cells (EPCs) or bone marrow-derived mesenchymal stem cells (BMSCs), and plays a central role in the process of neovascularization. In vivo or in vitro experiments show that bone distraction can induce the expression of SDF-1 and increase its plasma concentration. Moreover, some researchers have found that an insufficient level of SDF-1 in the circulation and wounds of patients with DFU can lead to impaired neovascularization. Therefore, we believe that SDF-1 plays an important role in promoting neovascularization of DFU as a result of bone distraction. We summarize the currently relevant literature to put forward an undisclosed but meaningful mechanism of bone distraction in the treatment of DFU.
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Affiliation(s)
- Jiezhuang Fang
- Department of Orthopedics, the First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Jiankun Xu
- Department of Orthopedics, the First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Yuantao Zhang
- Department of Orthopedics, the First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Hongjiang Chen
- Department of Orthopedics, the First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Zebin Ma
- Department of Orthopedics, the First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Zhonglian Huang
- Department of Orthopedics, the First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Jun Hu
- Department of Orthopedics, the First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
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9
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Chang M, Lin H, Fu H, Wang J, Yang Y, Wan Z, Han G. CREB activation affects mesenchymal stem cell migration and differentiation in periodontal tissues due to orthodontic force. Int J Biochem Cell Biol 2020; 129:105862. [PMID: 33045372 DOI: 10.1016/j.biocel.2020.105862] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 09/30/2020] [Accepted: 10/02/2020] [Indexed: 12/31/2022]
Abstract
During the orthodontic tooth movement, cells in periodontal ligament could differentiate into osteoblasts to synthesize alveolar bone as well as affect the proliferation, migration and differentiation of mesenchymal stem cells, which also contribute to bone remodeling. However, the mechanism is still largely elusive. Here, we evaluated the expression of CREB at the tension site of mouse periodontal ligament under orthodontic mechanical strain and in the cyclic tension strain treated human periodontal ligament cells. Then, through gain and loss of function analysis, we revealed that CREB in PDLCs promotes SDF-1 and FGF2 secretion, which enhance the migration and osteoblastic differentiation of BMSCs. We further discovered that CREB transcriptionally activates FGF2 and SDF-1 expressions by binding to the promoter regions.In conclusion, this study confirms that CREB is an upregulated gene in periodontal ligament under orthodontic tension strain stimulation and plays an important role in regulating BMSCs' physiological activity in orthodontic tension strain-induced bone formation.
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Affiliation(s)
- Maolin Chang
- State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Heng Lin
- State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Haidi Fu
- State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Jie Wang
- State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Yang Yang
- State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Ziqiu Wan
- State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Guangli Han
- State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
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10
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Xue Y, Li Z, Wang Y, Zhu X, Hu R, Xu W. Role of the HIF‑1α/SDF‑1/CXCR4 signaling axis in accelerated fracture healing after craniocerebral injury. Mol Med Rep 2020; 22:2767-2774. [PMID: 32945380 PMCID: PMC7453606 DOI: 10.3892/mmr.2020.11361] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 06/22/2020] [Indexed: 12/21/2022] Open
Abstract
The hypoxic state of the brain tissue surrounding craniocerebral injury induces an increase in the secretion of HIF-1α during the healing process. HIF-1α can promote mesenchymal stem cell (MSC) migration to ischemic and hypoxic sites by regulating the expression levels of molecules such as stromal cell-derived factor-1 (SDF-1) in the microenvironment. Stem cells express the SDF-1 receptor C-X-C chemokine receptor type 4 (CXCR4) and serve a key role in tissue repair, as well as a number of physiological and pathological processes. The present study aimed to determine the role of HIF-1α/SDF-1/CXCR4 signaling in the process of accelerated fracture healing during craniocerebral injury. Cultured MSCs underwent HIF-1α knockdown to elucidate its effect on the proliferative ability of MSCs, and the effect of SDF-1 in MSCs was investigated. It was also determined whether HIF-1α could promote osteogenesis via SDF-1/CXCR4 signaling and recruit MSCs. The results indicated that HIF-1α knockdown suppressed MSC proliferation in vitro, and SDF-1 promoted cell migration via binding to CXCR4. Furthermore, HIF-1α knockdown inhibited MSC migration via SDF-1/CXCR4 signaling. Considering the wide distribution and diversity of roles of SDF-1 and CXCR4, the present results may form a basis for the development of novel strategies for the treatment of craniocerebral injury.
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Affiliation(s)
- Yonghua Xue
- Department of Neurosurgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Zhikun Li
- Department of Orthopedic Surgery, Tongren Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 200331, P.R. China
| | - Yi Wang
- Department of Orthopedic Surgery, Tongren Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 200331, P.R. China
| | - Xiaodong Zhu
- Department of Orthopedic Surgery, Tongren Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 200331, P.R. China
| | - Ruixi Hu
- Department of Orthopedic Surgery, Tongren Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 200331, P.R. China
| | - Wei Xu
- Department of Orthopedic Surgery, Tongren Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 200331, P.R. China
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11
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De Paepe ME, Wong T, Chu S, Mao Q. Stromal cell-derived factor-1 (SDF-1) expression in very preterm human lungs: potential relevance for stem cell therapy for bronchopulmonary dysplasia. Exp Lung Res 2020; 46:146-156. [PMID: 32281423 DOI: 10.1080/01902148.2020.1751899] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Background: The axis formed by CXC chemokine receptor 4 (CXCR4), expressed on mesenchymal stromal cells (MSCs), and stromal cell-derived factor-1 (SDF-1), expressed in recipient organs, is a critical mediator of MSC migration in non-pulmonary injury models. The role and regulation of SDF-1 expression in preterm lungs, of potential relevance for MSC-based cell therapy for bronchopulmonary dysplasia (BPD), is unknown. The aim of this study was to determine the spatiotemporal pattern of CXCR4/SDF-1 expression in lungs of extremely preterm infants at risk for BPD.Methods: Postmortem lung samples were collected from ventilated extremely preterm infants who died between 23 and 29 wks ("short-term ventilated") or between 36 and 39 wks ("long-term ventilated") corrected postmenstrual age. Results were compared with age-matched infants who had lived <12 h or stillborn infants ("early" and "late" controls). CXCR4 and SDF-1 expression was studied by immunohistochemistry, immunofluorescence/confocal microscopy, and qRT-PCR analysis.Results: Compared with age-matched controls without antenatal infection, lungs of early control infants with evidence of intrauterine infection/inflammation showed significant upregulation of SDF-1 expression, localized to the respiratory epithelium, and of CXCR4 expression, localized to stromal cells. Similarly, pulmonary SDF-1 mRNA levels were significantly higher in long-term ventilated ex-premature infants with established BPD than in age-matched controls. The pulmonary vasculature was devoid of SDF-1 expression at all time points. Endogenous CXCR4-positive stromal cells were preferentially localized along the basal aspect of SDF-1-positive bronchial and respiratory epithelial cells, suggestive of functionality of the CXCR4/SDF-1 axis.Conclusions: Incipient and established neonatal lung injury is associated with upregulation of SDF-1 expression, restricted to the respiratory epithelium. Knowledge of the clinical associations, time-course and localization of pulmonary SDF-1 expression may guide decisions about the optimal timing and delivery route of MSC-based cell therapy for BPD.
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Affiliation(s)
- Monique E De Paepe
- Department of Pathology and Laboratory Medicine, Women and Infants Hospital, Alpert Medical School of Brown University, Providence, RI, USA
| | - Talia Wong
- Department of Pathology and Laboratory Medicine, Women and Infants Hospital, Alpert Medical School of Brown University, Providence, RI, USA
| | - Sharon Chu
- Department of Pathology and Laboratory Medicine, Women and Infants Hospital, Alpert Medical School of Brown University, Providence, RI, USA
| | - Quanfu Mao
- Department of Pathology and Laboratory Medicine, Women and Infants Hospital, Alpert Medical School of Brown University, Providence, RI, USA
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Tao YC, Chen EQ. Clinical application of stem cell in patients with end-stage liver disease: progress and challenges. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:564. [PMID: 32775365 PMCID: PMC7347777 DOI: 10.21037/atm.2020.03.153] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Accepted: 03/11/2020] [Indexed: 02/05/2023]
Abstract
End-stage liver disease (ESLD) is life-threatening disease worldwide, and patients with ESLD should be referred to liver transplantation (LT). However, the use of LT is limited by the lacking liver source, high cost and organ rejection. Thus, other alternative options have been explored. Stem cell therapy may be a potential alternative for ESLD treatment. With the potential of self-renewal and differentiation, both hepatic and extrahepatic stem cells have attracted a lot of attention. Among them, multipotent stem cells are most widely studies owing to their characteristics. Multipotent stem cells mainly consist of two subpopulations: hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). Accumulating evidences have proved that either bone marrow (BM)-derived HSCs mobilized by granulocyte colony-stimulating factor or MSCs transplantation can improve the biochemical indicators of patients with ESLD. However, there are some challenges to be resolved before stem cells widely used in clinic, including the best stem cell source, the optimal route for stem cells transplantation, and the dose and frequency of stem cell injected. The purpose of this review is to discuss the potential of stem cell in liver diseases, particularly, the clinical progress and challenges of multipotent stem cells in the field of ESLD.
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Affiliation(s)
- Ya-Chao Tao
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
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Bai WF, Zhang Y, Xu W, Li W, Li M, Yuan F, Luo X, Zhang M. Isolation and Characterization of Neural Progenitor Cells From Bone Marrow in Cell Replacement Therapy of Brain Injury. Front Cell Neurosci 2020; 14:49. [PMID: 32226361 PMCID: PMC7080866 DOI: 10.3389/fncel.2020.00049] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 02/21/2020] [Indexed: 12/27/2022] Open
Abstract
Many studies supported that bone marrow mesenchymal stem cells (BM-MSCs) can differentiate into neural cells, but few researchers detected mature and function of nerve cells, especially in vivo study. Some researchers even suggested that BM-MSCs transplantation would not be able to differentiate into functional neural cells. To figure out the dispute, this study examined bone marrow-derived sphere-like cells, harvested via neural stem cell suspension culture, then identified as bone marrow-derived neural progenitor cells (BM-NPCs) by finding the expression of neural progenitor cells genes and proteins, neural progenitor cells characteristic and nerve cell differentiation induced through both methods. Moreover, BM-NPCs transplantation showed long-term survival and improved the ethological and histological indexes of brain injury rats, demonstrating functional nervous cells differentiated from BM-NPCs. These in vitro and in vivo results confirmed BM-NPCs differentiating into mature and functional nerve cells. This study provided valuable experimental data for BM-NPCs, suggesting a potential alternative treatment of central nervous injury disease.
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Affiliation(s)
- Wen-fang Bai
- Department of Rehabilitation Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangdong Provincial Institute of Geriatrics, Guangzhou, China
| | - Yuling Zhang
- School of Medical Instrument and Food Engineering, The University of Shanghai for Science and Technology, Shanghai, China
- Stroke Biological Recovery Laboratory, Spaulding Rehabilitation Hospital, a Teaching Affiliate of Harvard Medical School, Charlestown, MA, United States
| | - Weicheng Xu
- Department of Rehabilitation Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangdong Provincial Institute of Geriatrics, Guangzhou, China
| | - Weikun Li
- Department of Rehabilitation Medicine, Zengcheng District People’s Hospital of Guangzhou, Guangzhou, China
| | - Meihui Li
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Fengying Yuan
- Department of Rehabilitation Medicine, Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Foshan, China
| | - Xun Luo
- Kerry Rehabilitation Medicine Research Institute, Shenzhen, China
- Shenzhen Sanming Project Group, Spaulding Rehabilitation Hospital, a Teaching Affiliate of Harvard Medical School, Charlestown, MA, United States
| | - Mingsheng Zhang
- Department of Rehabilitation Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangdong Provincial Institute of Geriatrics, Guangzhou, China
- *Correspondence: Mingsheng Zhang
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Chu X, Karasinski K, Donellan S, Kaniper S, Wood GC, Shi W, Edwards MA, Soans R, Still CD, Gerhard GS. A retrospective case control study identifies peripheral blood mononuclear cell albumin RNA expression as a biomarker for non-alcoholic fatty liver disease. Langenbecks Arch Surg 2019; 405:165-172. [PMID: 31828503 DOI: 10.1007/s00423-019-01848-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 11/28/2019] [Indexed: 12/20/2022]
Abstract
PURPOSE Non-alcoholic fatty liver disease (NAFLD) improves after bariatric surgery. The aim of this study was to determine whether peripheral blood mononuclear cell albumin gene expression was related to NAFLD and whether albumin (ALB) and alpha fetoprotein (AFP) expression could be detected in whole blood and visceral adipose tissue. METHODS Using a retrospective case control study design, RNA isolated from peripheral blood mononuclear cells from patients prior to undergoing bariatric surgery was used for pooled microarray analysis. Quantitative polymerase chain reaction (QPCR) was used to analyze whole blood and visceral adipose tissue. Liver histology was obtained via intra-operative biopsy and clinical data extracted from the electronic health record. RESULTS The albumin (ALB) gene was the second most up-regulated found in microarray analysis of peripheral blood mononuclear cell RNA from patients with hepatic lobular inflammation versus normal liver histology. Transcript levels of ALB were significantly different across those with normal (n = 50), steatosis (n = 50), lobular inflammation (n = 50), and peri-sinusoidal fibrosis (n = 50) liver histologies, with lobular inflammation 3.9 times higher than those with normal histology (p < 0.017). Albumin expression levels decreased in 11/13 patients in paired samples obtained prior to and at 1 year after Roux-en-Y gastric bypass surgery. ALB expression could be detected in 23 visceral adipose tissue samples obtained intra-operatively and in 18/19 available paired whole blood samples. No significant correlation was found between ALB expression in visceral adipose tissue and whole blood RNA samples. Alpha fetoprotein expression as a marker of early hepatocytic differentiation was detected in 17/17 available VAT RNA samples, but in only 2/17 whole blood RNA samples. CONCLUSION Albumin RNA expression from blood cells may serve as a biomarker of NAFLD. Albumin and alpha fetoprotein appear to be ubiquitously expressed in visceral adipose tissue in patients with extreme obesity.
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Affiliation(s)
- Xin Chu
- Obesity Research Institute, Geisinger Clinic, Danville, PA, USA
| | - Kelsey Karasinski
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Philadelphia, PA, 19140, USA
| | - Sean Donellan
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Philadelphia, PA, 19140, USA
| | - Scott Kaniper
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Philadelphia, PA, 19140, USA
| | - G Craig Wood
- Obesity Research Institute, Geisinger Clinic, Danville, PA, USA
| | - Weixing Shi
- Obesity Research Institute, Geisinger Clinic, Danville, PA, USA
| | - Michael A Edwards
- Department of Surgery, Lewis Katz School of Medicine, Philadelphia, PA, 19140, USA
| | - Rohit Soans
- Department of Surgery, Lewis Katz School of Medicine, Philadelphia, PA, 19140, USA
| | | | - Glenn S Gerhard
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Philadelphia, PA, 19140, USA.
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Stem Cell Mobilization Is Lifesaving in a Large Animal Preclinical Model of Acute Liver Failure. Ann Surg 2019; 268:620-631. [PMID: 30102635 DOI: 10.1097/sla.0000000000002958] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Acute liver failure (ALF) affects 2000 Americans each year with no treatment options other than liver transplantation. We showed previously that mobilization of endogenous stem cells is protective against ALF in rodents. The objective of this study was to assess whether stem cell mobilizing drugs are lifesaving in a large animal preclinical model of ALF, to assess readiness for a clinical trial. METHODS Male Yorkshire pigs (14-18 kg) were divided into 2 groups, control (n = 6) and treatment (n = 6). All pigs received an intravenous bolus of the hepatotoxin D-galactosamine (0.5 g/kg) via central line and were followed up until death or day 28. Treated animals received simultaneous intramuscular injection of plerixafor (1 mg/kg) and G-CSF (2 μg/kg) at baseline, 24 and 48 hours after toxin infusion to mobilize endogenous stem cells, as previously described. Control animals received saline. RESULTS All control animals (6/6) succumbed to liver failure within 91 hours, confirmed by clinical, biochemical, and histopathological evidence of ALF. In the treatment group (5/6) animals survived indefinitely despite comparable biochemical changes during the first 48 hours (P = 0.003). White blood cell count increased by a mean of 4× in the treated group at the peak of mobilization (P = 0.0004). CONCLUSIONS Stem cell mobilizing drugs were lifesaving in a preclinical large animal model of ALF. Since no therapeutic options other than liver transplantation are currently available for critically ill patients with ALF, a multicenter clinical trial is warranted.
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Wang X, Jiang B, Sun H, Zheng D, Zhang Z, Yan L, Li E, Wu Y, Xu RH. Noninvasive application of mesenchymal stem cell spheres derived from hESC accelerates wound healing in a CXCL12-CXCR4 axis-dependent manner. Theranostics 2019; 9:6112-6128. [PMID: 31534540 PMCID: PMC6735514 DOI: 10.7150/thno.32982] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 06/29/2019] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSC) derived from adult tissues effectively promote wound healing. However, MSC quality varies, and the quantity of MSC is limited, as MSC are acquired through donations. Moreover, the survival and functioning of dissociated MSC delivered to an inflammatory lesion are subject to challenges. Methods: Here, spheres (EMSCSp) generated from human embryonic stem cell-derived MSC (EMSC) were directly dropped onto excised wounds in mice; the effects of EMSCSp were compared to those of dissociated EMSC (EMSCDiss). Following transplantation, we measured the extent of wound closure, dissected the histological features of the wounds, determined transcriptomic changes in cells isolated from the treated and control wounds, and evaluated the molecular mechanism of the effects of EMSC. Results: The application of EMSCSp onto murine dermal wounds substantially increased survival and efficacy of EMSC compared to the topical application of EMSCDiss. RNA sequencing (RNA-Seq) of cells isolated from the wounds highlighted the involvement of CXCL12-CXCR4 signaling in the effects of EMSCSp, which was verified in EMSC via CXCL12 knockdown and in target cells (vascular endothelial cells, epithelial keratinocytes, and macrophages) via CXCR4 inhibition. Finally, we enhanced the biosafety of EMSCSp by engineering cells with an inducible suicide gene. Conclusions: Together, these data suggest the topical application of EMSCSp as an unlimited, quality-assured, safe, and noninvasive therapy for wound healing and the CXCL12-CXCR4 axis as a key player in this treatment.
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Affiliation(s)
- Xiaoyan Wang
- Center of Reproduction, Development & Aging, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Bin Jiang
- Center of Reproduction, Development & Aging, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Huiyan Sun
- Center of Reproduction, Development & Aging, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
- School of Artificial Intelligence, Jilin University, Changchun, China
| | - Dejin Zheng
- Center of Reproduction, Development & Aging, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Zhenwu Zhang
- Center of Reproduction, Development & Aging, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Li Yan
- Center of Reproduction, Development & Aging, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Enqin Li
- Center of Reproduction, Development & Aging, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Yaojiong Wu
- The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Shenzhen, China
| | - Ren-He Xu
- Center of Reproduction, Development & Aging, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
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Yu Z, Xu N, Zhang N, Xiong Y, Wang Z, Liang S, Zhao D, Huang F, Zhang C. Repair of Peripheral Nerve Sensory Impairments via the Transplantation of Bone Marrow Neural Tissue-Committed Stem Cell-Derived Sensory Neurons. Cell Mol Neurobiol 2019; 39:341-353. [PMID: 30684112 PMCID: PMC11469867 DOI: 10.1007/s10571-019-00650-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 01/04/2019] [Indexed: 01/20/2023]
Abstract
The present study aimed to investigate the efficacy of transplantation of bone marrow neural tissue-committed stem cell-derived sensory neuron-like cells for the repair of peripheral nerve sensory impairments in rats. Bone marrow was isolated and cultured to obtain the neural tissue-committed stem cells (NTCSCs), and the differentiation of these cells into sensory neuron-like cells was induced. Bone marrow mesenchymal stem cells (BMSCs), bone marrow NTCSCs, and bone marrow NTCSC-derived sensory neurons (NTCSC-SNs) were transplanted by microinjection into the L4 and L5 dorsal root ganglions (DRGs) in an animal model of sensory defect. On the 2nd, 4th, 8th, and 12th week after the transplantation, the effects of the three types of stem cells on the repair of the sensory functional defect were analyzed via behavioral observation, sensory function evaluation, electrophysiological examination of the sciatic nerve, and morphological observation of the DRGs. The results revealed that the transplanted BMSCs, NTCSCs, and NTCSC-SNs were all able to repair the sensory nerves. In addition, the effect of the NTCSC-SNs was significantly better than that of the other two types of stem cells. The general posture and gait of the animals in the sensory defect model exhibited evident improvement over time. Plantar temperature sensitivity and pain sensitivity gradually recovered, and the sensation latency was reduced, with faster sensory nerve conduction velocity. Transplantation of NTCSC-SNs can improve the repair of peripheral nerve sensory defects in rats.
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Affiliation(s)
- Zhenhai Yu
- Department of Human Anatomy, College of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, People's Republic of China
- Department of Human Anatomy, College of Basic Medical Sciences, Second Military Medical University, Shanghai, 200433, People's Republic of China
| | - Ning Xu
- Department of Gastroenterology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264100, People's Republic of China
| | - Naili Zhang
- Department of Human Anatomy, College of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, People's Republic of China
| | - Yanlian Xiong
- Department of Human Anatomy, College of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, People's Republic of China
| | - Zhiqiang Wang
- Department of Human Anatomy, College of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, People's Republic of China
| | - Shaohua Liang
- Department of Human Anatomy, College of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, People's Republic of China
| | - Dongmei Zhao
- Department of Human Anatomy, College of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, People's Republic of China
| | - Fei Huang
- Department of Human Anatomy, College of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, People's Republic of China.
| | - Chuansen Zhang
- Department of Human Anatomy, College of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, People's Republic of China.
- Department of Human Anatomy, College of Basic Medical Sciences, Second Military Medical University, Shanghai, 200433, People's Republic of China.
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Paudel S, Lee WH, Lee M, Zahoor T, Mitchell R, Yang SY, Zhao H, Schon L, Zhang Z. Intravenous administration of multipotent stromal cells and bone allograft modification to enhance allograft healing. Regen Med 2019; 14:199-211. [PMID: 30761943 DOI: 10.2217/rme-2018-0063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: This study investigated a coordinated strategy of revitalizing bone allograft with circulating multipotent stromal cells (MSCs). Materials & methods: After chemotactic and releasing assessments, stromal cell-derived factor 1 and platelet-derived growth factor BB in copolymers were coated on the bone allograft (AlloS-P). Allograft coated with copolymers alone (Allo), as controls, or AlloS-P was implanted into the femur of athymic mice, which received intravenous injections of human MSCs or saline at weeks 1, 2 and 3. Results: At week 8, the total callus volume (both cartilaginous and bony callus) around the allograft was the largest in the AlloS-P + MSC group (p < 0.05). Conclusion: Coating bone allograft with stromal cell-derived factor 1 and platelet-derived growth factor BB and intravenous injections of MSCs improved allograft incorporation.
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Affiliation(s)
- Sharada Paudel
- Orthobiologic Laboratory, MedStar Union Memorial Hospital, Baltimore, MD, USA
| | - Wen-Han Lee
- Orthobiologic Laboratory, MedStar Union Memorial Hospital, Baltimore, MD, USA
| | - Moses Lee
- Orthobiologic Laboratory, MedStar Union Memorial Hospital, Baltimore, MD, USA
| | - Talal Zahoor
- Orthobiologic Laboratory, MedStar Union Memorial Hospital, Baltimore, MD, USA
| | - Reed Mitchell
- Orthobiologic Laboratory, MedStar Union Memorial Hospital, Baltimore, MD, USA
| | - Shang-You Yang
- Department of Orthopaedic Surgery, University of Kansas School of Medicine-Wichita, Wichita, KS, USA
| | - Haiqing Zhao
- Department of Biology, Johns Hopkins University, Baltimore, MD, USA
| | - Lew Schon
- Orthobiologic Laboratory, MedStar Union Memorial Hospital, Baltimore, MD, USA
| | - Zijun Zhang
- Orthobiologic Laboratory, MedStar Union Memorial Hospital, Baltimore, MD, USA
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Gizaw M, Faglie A, Pieper M, Poudel S, Chou SF. The Role of Electrospun Fiber Scaffolds in Stem Cell Therapy for Skin Tissue Regeneration. MED ONE 2019; 4:e190002. [PMID: 30972372 PMCID: PMC6453140 DOI: 10.20900/mo.20190002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Stem cell therapy has emerged as one of the topics in tissue engineering where undifferentiated and multipotent cells are strategically placed/ injected in tissue structure for cell regeneration. Over the years, stem cells have shown promising results in skin repairs for non-healing and/or chronic wounds. The addition of the stem cells around the wound site promotes signaling pathways for growth factors that regulate tissue reconstruction. However, injecting stem cells around the wound site has its drawbacks, including cell death due to lack of microenvironment cues. This particular issue is resolved when biomaterial scaffolds are involved in the cultivation and mechanical support of the stem cells. In this review, we describe the current models of stem cell therapy by injections and those that are done through cell cultures using electrospun fiber scaffolds. Electrospun fibers are considered as an ideal candidate for cell cultures due to their surface properties. Through the control of fiber morphology and fiber structure, cells are able to proliferate and differentiate into keratinocytes for skin tissue regeneration. Furthermore, we provide another perspective of using electrospun fibers and stem cells in a layer-by-layer structure for skin substitutes (dressing). Finally, electrospun fibers have the potential to incorporate bioactive agents to achieve controlled release properties, which is beneficial to the survival of the delivered stem cells or the recruitment of the cells. Overall, our work illustrates that electrospun fibers are ideal for stem cell cultures while serving as cell carriers for wound dressing materials.
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Affiliation(s)
- Mulugeta Gizaw
- Department of Mechanical Engineering, College of Engineering, The University of Texas at Tyler, Tyler, TX 75799, USA
| | - Addison Faglie
- Department of Mechanical Engineering, College of Engineering, The University of Texas at Tyler, Tyler, TX 75799, USA
| | - Martha Pieper
- Department of Mechanical Engineering, College of Engineering, The University of Texas at Tyler, Tyler, TX 75799, USA
| | - Sarju Poudel
- Department of Mechanical Engineering, College of Engineering, The University of Texas at Tyler, Tyler, TX 75799, USA
| | - Shih-Feng Chou
- Department of Mechanical Engineering, College of Engineering, The University of Texas at Tyler, Tyler, TX 75799, USA
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Van SY, Noh YK, Kim SW, Oh YM, Kim IH, Park K. Human umbilical cord blood mesenchymal stem cells expansion via human fibroblast-derived matrix and their potentials toward regenerative application. Cell Tissue Res 2019; 376:233-245. [PMID: 30610451 DOI: 10.1007/s00441-018-2971-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 11/23/2018] [Indexed: 12/11/2022]
Abstract
Large expansion of human mesenchymal stem cells (MSCs) is of great interest for clinical applications. In this study, we examine the feasibility of human fibroblast-derived extracellular matrix (hFDM) as an alternative cell expansion setting. hFDM is obtained from decellularized extracellular matrix (ECM) derived from in vitro cultured human lung fibroblasts. Our study directly compares conventional platforms (tissue culture plastic (TCP), fibronectin (FN)-coated TCP) with hFDM using umbilical cord blood-derived MSCs (UCB-MSCs). Early cell morphology shows a rather rounded shape on TCP but highly elongated morphology on hFDM. Cell proliferation demonstrates that MSCs on hFDM were significantly better compared to the others in both 10 and 2% serum condition. Cell migration assay suggests that cell motility was improved and a cell migration marker CXCR4 was notably up-regulated on hFDM. MSCs differentiation into osteogenic lineage on hFDM was also very effective as examined via gene expression, von Kossa staining and alkaline phosphatase activity. In addition, as the MSCs were expanded on each substrate, transferred to 3D polymer mesh scaffolds and then cultivated for a while, the data found better cell proliferation and more CXCR4 expression with MSCs pre-conditioned on hFDM. Moreover, higher gene expression of stemness and engraftment-related markers was noticed with the hFDM group. Furthermore when UCB-MSCs expanded on TCP or hFDM were injected into emphysema (a lung disease) animal model, the results indicate that MSCs pre-conditioned on hFDM (with 2% serum) retain more advanced therapeutic efficacy on the improvement of emphysema than those on TCP. Current works demonstrate that compared to the conventional platforms, hFDM can be a promising source of cell expansion with a naturally derived biomimetic ECM microenvironment and may find some practical applications in regenerative medicine.
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Affiliation(s)
- Se Young Van
- Center for Biomaterials, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
| | - Yong Kwan Noh
- Center for Biomaterials, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea.,Department of Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Seong Who Kim
- Department of Biochemistry and Molecular Biology, College of Medicine, Asan Medical Center, University of Ulsan, Seoul, 05505, Republic of Korea
| | - Yeon Mok Oh
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
| | - Ik Hwan Kim
- Department of Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
| | - Kwideok Park
- Center for Biomaterials, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea. .,Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology (UST), Seoul, 02792, Republic of Korea.
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Jin W, Liang X, Brooks A, Futrega K, Liu X, Doran MR, Simpson MJ, Roberts MS, Wang H. Modelling of the SDF-1/CXCR4 regulated in vivo homing of therapeutic mesenchymal stem/stromal cells in mice. PeerJ 2018; 6:e6072. [PMID: 30564525 PMCID: PMC6286806 DOI: 10.7717/peerj.6072] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 11/05/2018] [Indexed: 01/12/2023] Open
Abstract
Background Mesenchymal stem/stromal cells (MSCs) are a promising tool for cell-based therapies in the treatment of tissue injury. The stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis plays a significant role in directing MSC homing to sites of injury. However in vivo MSC distribution following intravenous transplantation remains poorly understood, potentially hampering the precise prediction and evaluation of therapeutic efficacy. Methods A murine model of partial ischemia/reperfusion (I/R) is used to induce liver injury, increase the hepatic levels of SDF-1, and study in vivo MSC distribution. Hypoxia-preconditioning increases the expression of CXCR4 in human bone marrow-derived MSCs. Quantitative assays for human DNA using droplet digital PCR (ddPCR) allow us to examine the in vivo kinetics of intravenously infused human MSCs in mouse blood and liver. A mathematical model-based system is developed to characterize in vivo homing of human MSCs in mouse models with SDF-1 levels in liver and CXCR4 expression on the transfused MSCs. The model is calibrated to experimental data to provide novel estimates of relevant parameter values. Results Images of immunohistochemistry for SDF-1 in the mouse liver with I/R injury show a significantly higher SDF-1 level in the I/R injured liver than that in the control. Correspondingly, the ddPCR results illustrate a higher MSC concentration in the I/R injured liver than the normal liver. CXCR4 is overexpressed in hypoxia-preconditioned MSCs. An increased number of hypoxia-preconditioned MSCs in the I/R injured liver is observed from the ddPCR results. The model simulations align with the experimental data of control and hypoxia-preconditioned human MSC distribution in normal and injured mouse livers, and accurately predict the experimental outcomes with different MSC doses. Discussion The modelling results suggest that SDF-1 in organs is an effective in vivo attractant for MSCs through the SDF-1/CXCR4 axis and reveal the significance of the SDF-1/CXCR4 chemotaxis on in vivo homing of MSCs. This in vivo modelling approach allows qualitative characterization and prediction of the MSC homing to normal and injured organs on the basis of clinically accessible variables, such as the MSC dose and SDF-1 concentration in blood. This model could also be adapted to abnormal conditions and/or other types of circulating cells to predict in vivo homing patterns.
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Affiliation(s)
- Wang Jin
- School of Mathematical Sciences, Queensland University of Technology, Brisbane, Australia
| | - Xiaowen Liang
- Therapeutics Research Centre, The University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia
| | - Anastasia Brooks
- Therapeutics Research Centre, The University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia
| | - Kathryn Futrega
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, Australia
| | - Xin Liu
- Therapeutics Research Centre, The University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia
| | - Michael R Doran
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, Australia.,Mater Research Institute, University of Queensland, Translational Research Institute, Brisbane, Australia.,Australian National Centre for the Public Awareness of Science, Australian National University, Canberra, Australia
| | - Matthew J Simpson
- School of Mathematical Sciences, Queensland University of Technology, Brisbane, Australia
| | - Michael S Roberts
- Therapeutics Research Centre, The University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia.,School of Pharmacy and Medical Science, University of South Australia, Adelaide, Australia
| | - Haolu Wang
- Therapeutics Research Centre, The University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia
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22
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Thakkar SH, Di Luca A, Zaccaria S, Baaijens FPT, Bouten CVC, Dankers PYW. Dual Electrospun Supramolecular Polymer Systems for Selective Cell Migration. Macromol Biosci 2018; 18:e1800004. [PMID: 29870589 DOI: 10.1002/mabi.201800004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 03/23/2018] [Indexed: 11/10/2022]
Abstract
Dual electrospinning can be used to make multifunctional scaffolds for regenerative medicine applications. Here, two supramolecular polymers with different material properties are electrospun simultaneously to create a multifibrous mesh. Bisurea (BU)-based polycaprolactone, an elastomer providing strength to the mesh, and ureido-pyrimidinone (UPy) modified poly(ethylene glycol) (PEG), a hydrogelator, introducing the capacity to deliver compounds upon swelling. The dual spun scaffolds are modularly tuned by mixing UPyPEG hydrogelators with different polymer lengths, to control swelling of the hydrogel fiber, while maintaining the mechanical properties of the scaffold. Stromal cell derived factor 1 alpha (SDF1α) peptides are embedded in the UPyPEG fibers. The swelling and erosion of UPyPEG increase void spaces and released the SDF1α peptide. The functionalized scaffolds demonstrate preferential lymphocyte recruitment proposed to be created by a gradient formed by the released SDF1α peptide. This delivery approach offers the potential to develop multifibrous scaffolds with various functions.
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Affiliation(s)
- Shraddha H Thakkar
- Department of Biomedical Engineering, Soft Tissue Biomechanics & Tissue Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands
| | - Andrea Di Luca
- Department of Biomedical Engineering, Soft Tissue Biomechanics & Tissue Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands
| | - Sabrina Zaccaria
- Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands
| | - Frank P T Baaijens
- Department of Biomedical Engineering, Soft Tissue Biomechanics & Tissue Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands
| | - Carlijn V C Bouten
- Department of Biomedical Engineering, Soft Tissue Biomechanics & Tissue Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands
| | - Patricia Y W Dankers
- Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands
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Abstract
Purpose of Review The aim of the study is to provide an overview on the possibility of treating congenital disorders prenatally with mesenchymal stromal cells (MSCs). Recent Findings MSCs have multilineage potential and a low immunogenic profile and are immunomodulatory and more easy to expand in culture. Their ability to migrate, engraft and differentiate, or act via a paracrine effect on target tissues makes MSCs candidates for clinical therapies. Fetal and extra-fetal MSCs offer higher therapeutic potential compared to MSCs derived from adult sources. Summary MSCs may be safely transplanted prenatally via ultrasound-guided injection into the umbilical cord. Due to these characteristics, fetal MSCs are of great interest in the field of in utero stem cell transplantation for treatment of congenital disease.
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24
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Tishevskaya NV, Babaeva AG, Gevorkyan NM. Effect of lymphocyte morphogenetic activity on organism reactivity and resistibility. Russ J Dev Biol 2018. [DOI: 10.1134/s106236041801006x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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25
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Wang R, Liu W, Du M, Yang C, Li X, Yang P. The differential effect of basic fibroblast growth factor and stromal cell‑derived factor‑1 pretreatment on bone morrow mesenchymal stem cells osteogenic differentiation potency. Mol Med Rep 2017; 17:3715-3721. [PMID: 29359787 PMCID: PMC5802181 DOI: 10.3892/mmr.2017.8316] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 11/03/2017] [Indexed: 12/17/2022] Open
Abstract
In situ tissue engineering has become a novel strategy to repair periodontal/bone tissue defects. The choice of cytokines that promote the recruitment and proliferation, and potentiate and maintain the osteogenic differentiation ability of mesenchymal stem cells (MSCs) is the key point in this technique. Stromal cell‑derived factor‑1 (SDF‑1) and basic fibroblast growth factor (bFGF) have the ability to promote the recruitment, and proliferation of MSCs; however, the differential effect of SDF‑1 and bFGF pretreatment on MSC osteogenic differentiation potency remains to be explored. The present study comparatively observed osteogenic differentiation of bone morrow MSCs (BMMSCs) pretreated by bFGF or SDF‑1 in vitro. The gene and protein expression levels of alkaline phosphatase (ALP), runt related transcription factor 2 (Runx‑2) and bone sialoprotein (BSP) were detected using reverse transcription‑quantitative polymerase chain reaction and western blotting. The results showed that the expression of ALP mRNA on day 3, and BSP and Runx‑2 mRNA on day 7 in the bFGF pretreatment group was significantly higher than those in SDF‑1 pretreatment group. Expression levels of Runx‑2 mRNA, and ALP and Runx‑2 protein on day 3 in the SDF‑1 pretreatment group were higher than those in the bFGF pretreatment group. However, there was no significant difference in osteogenic differentiation ability on day 14 and 28 between the bFGF‑ or SDF‑1‑pretreatment groups and the control. In conclusion, bFGF and SDF‑1 pretreatment inhibits osteogenic differentiation of BMMSCs at the early stage, promotes it in the medium phase, and maintains it in the later stage during osteogenic induction, particularly at the mRNA level. Out of the two cytokines, bFGF appeared to have a greater effect on osteogenic differentiation.
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Affiliation(s)
- Ruolin Wang
- Department of Periodontology, School of Stomatology, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Wenhua Liu
- Department of Periodontology, School of Stomatology, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Mi Du
- Department of Periodontology, School of Stomatology, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Chengzhe Yang
- Department of Oral and Maxillofacial Surgery, Qilu Hospital and Institute of Stomatology, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Xuefen Li
- Department of Periodontology, School of Stomatology, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Pishan Yang
- Department of Periodontology, School of Stomatology, Shandong University, Jinan, Shandong 250012, P.R. China
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26
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Enzmann V, Lecaudé S, Kruschinski A, Vater A. CXCL12/SDF-1-Dependent Retinal Migration of Endogenous Bone Marrow-Derived Stem Cells Improves Visual Function after Pharmacologically Induced Retinal Degeneration. Stem Cell Rev Rep 2017; 13:278-286. [PMID: 27924617 DOI: 10.1007/s12015-016-9706-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Mobilized bone marrow-derived stem cells (BMSC) have been discussed as an alternative strategy for endogenous repair. Thereby, different approaches for BMSC mobilization have been pursued. Herein, the role of a newly discovered oligonucleotide for retinal homing and regeneration capability of BMSCs was investigated in the sodium iodate (NaIO3) model of retinal degeneration. Mobilization was achieved in GFP-chimera with NOX-A12, a CXC-motif chemokine ligand 12 (CXCL12)/stromal cell-derived factor 1 (SDF-1)-neutralizing L-aptamer. BMSC homing was directed by intravitreal SDF-1 injection. Visual acuity was measured using the optokinetic reflex. Paraffin cross sections were stained with hematoxylin and eosin for retinal thickness measurements. Immunohistochemistry was performed to investigate the expression of cell-specific markers after mobilization. A single dose of NOX-A12 induced significant mobilization of GFP+ cells which were found in all layers within the degenerating retina. An additional intravitreal injection of SDF-1 increased migration towards the site of injury. Thereby, the number of BMSCs (Sca-1+) found in the damaged retina increased whereas a decrease of activated microglia (Iba-1+) was found. The mobilization led to significantly increased visual acuity. However, no significant changes in retinal thickness or differentiation towards retinal cell types were detected. Systemic mobilization by a single dose of NOX-A12 showed increased homing of BMSCs into the degenerated retina, which was associated with improved visual function when injection of SDF-1 was additionally performed. The redistribution of the cells to the site of injury combined with their observed beneficial effects support the endogenous therapeutic strategy for retinal repair.
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Affiliation(s)
- Volker Enzmann
- Department of Ophthalmology, University Hospital, University of Bern, Freiburgstrasse 14, 3010, Bern, Switzerland. .,Department of Clinical Research, University of Bern, Bern, Switzerland.
| | - Stéphanie Lecaudé
- Department of Clinical Research, University of Bern, Bern, Switzerland
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Wang Y, Sun X, Lv J, Zeng L, Wei X, Wei L. Stromal Cell-Derived Factor-1 Accelerates Cartilage Defect Repairing by Recruiting Bone Marrow Mesenchymal Stem Cells and Promoting Chondrogenic Differentiation<sup/>. Tissue Eng Part A 2017; 23:1160-1168. [PMID: 28478702 DOI: 10.1089/ten.tea.2017.0046] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Chemokine stromal cell-derived factor-1 (SDF-1) is a powerful chemoattractant for the localization of CXCR4-positive bone marrow mesenchymal stem cells (BMSCs) into the bone marrow. We studied the effects of SDF-1 on the cartilage defect repair by recruiting BMSCs and promoting its chondrogenic differentiation in vitro and in vivo. Chemotaxis analysis with Transwell plate showed that SDF-1 could recruit BMSCs through SDF-1/CXCR4 axis. Real-time polymerase chain reaction, enzyme-linked immunosorbent assays, and Western blot results suggested that the levels of type II collagen and GAG were increased after incubating BMSCs with SDF-1 compared with the without SDF-1 group. More positive BrdU-labeled BMSCs were detected at the cartilage defect region in the SDF-1 + poly [lactide-co-glycolide] (PLGA) scaffold group (SP) in which those animals showed a smooth and transparent cartilage tissue with a strong staining of toluidine blue and type II collagen compared with the no-SDF-1 groups. ICRS score suggested that the repair effect in the SDF-1 + PLGA-treated animals was improved compared with PLGA scaffold group alone at 4 and 8 weeks after surgery; the repair effect from the SDF + PLGA-treated animals was significantly improved compared with the PLGA alone at 12 weeks after surgery. Our in vitro and in vivo results indicated the following: (1) SDF-1 could recruit the BMSCs into cartilage defect area. (2) SDF-1 induces BMSCs expressing type II collagen and GAG, which may accelerate the BMSCs transforming into chondrocytes under the cartilage microenvironment in vivo. (3) PLGA scaffold attached with SDF-1 remarkably promoted the cartilage defect repairing. The defected cartilage was filled with transparent cartilage 12 weeks after the surgery, which shared a similar structure with the adjacent normal cartilage. Taken together, this research provides a new strategy for cartilage defect repairing.
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Affiliation(s)
- Yuze Wang
- 1 Department of Orthopaedics, The Second Hospital of Shanxi Medical University , Taiyuan City, Shanxi Province, China
| | - Xiaojuan Sun
- 1 Department of Orthopaedics, The Second Hospital of Shanxi Medical University , Taiyuan City, Shanxi Province, China
| | - Jia Lv
- 1 Department of Orthopaedics, The Second Hospital of Shanxi Medical University , Taiyuan City, Shanxi Province, China
| | - Lingyuan Zeng
- 1 Department of Orthopaedics, The Second Hospital of Shanxi Medical University , Taiyuan City, Shanxi Province, China
| | - Xiaochun Wei
- 1 Department of Orthopaedics, The Second Hospital of Shanxi Medical University , Taiyuan City, Shanxi Province, China
| | - Lei Wei
- 1 Department of Orthopaedics, The Second Hospital of Shanxi Medical University , Taiyuan City, Shanxi Province, China .,2 Department of Orthopaedics, The Warren Alpert Medical School of Brown University/Rhode Island Hospital (RIH) , Providence, Rhode Island
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28
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Impaired mRNA Expression of the Migration Related Chemokine Receptor CXCR4 in Mesenchymal Stem Cells of COPD Patients. Int J Inflam 2017; 2017:6089425. [PMID: 28804668 PMCID: PMC5539942 DOI: 10.1155/2017/6089425] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 06/06/2017] [Indexed: 01/07/2023] Open
Abstract
Defective tissue repair and remodeling are main aspects of Chronic Obstructive Pulmonary Disease (COPD) pathophysiology. Bone marrow mesenchymal stem cells (BM-MSCs) have been implicated in this direction, as their functional impairment and recruitment could possibly contribute to disease development and progression. The present study characterizes for the first time the expression of migration related chemokine receptors and their ligands in BM-MSCs from COPD patients. CXCR4/SDF1a and CCR7/CCL19-CCL21 mRNA levels were evaluated in BM-MSCs obtained from twelve COPD patients and seven healthy donors. SDF1a protein levels in sera and BM-MSCs' conditioned media were also evaluated. CXCR4, SDF1a, CCL19, and CCL21 mRNA levels were significantly reduced in COPD BM-MSCs while CCR7 levels were undetectable. Notably, SDF1a protein levels were marginally elevated in both patient sera and BM-MSCs' conditioned media while the increase in SDF1a serum levels significantly correlated with disease severity in COPD. Our findings show posttranscriptional regulation of SDF1a levels in BM-MSCs of COPD patients and significant downregulation of SDF1a and CXCR4 mRNA indicating an involvement of the SDF1a signaling pathway in the disease pathophysiology.
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29
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Ljubimov AV. Cell Therapy for Age-Related Macular Degeneration: A New Vision for the Bone Marrow? Mol Ther 2017; 25:832-833. [PMID: 28318930 DOI: 10.1016/j.ymthe.2017.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Affiliation(s)
- Alexander V Ljubimov
- Eye Program, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, and David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90048, USA.
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30
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Qi X, Pay SL, Yan Y, Thomas J, Lewin AS, Chang LJ, Grant MB, Boulton ME. Systemic Injection of RPE65-Programmed Bone Marrow-Derived Cells Prevents Progression of Chronic Retinal Degeneration. Mol Ther 2017; 25:917-927. [PMID: 28202390 PMCID: PMC5383551 DOI: 10.1016/j.ymthe.2017.01.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Revised: 01/04/2017] [Accepted: 01/06/2017] [Indexed: 01/18/2023] Open
Abstract
Bone marrow stem and progenitor cells can differentiate into a range of non-hematopoietic cell types, including retinal pigment epithelium (RPE)-like cells. In this study, we programmed bone marrow-derived cells (BMDCs) ex vivo by inserting a stable RPE65 transgene using a lentiviral vector. We tested the efficacy of systemically administered RPE65-programmed BMDCs to prevent visual loss in the superoxide dismutase 2 knockdown (Sod2 KD) mouse model of age-related macular degeneration. Here, we present evidence that these RPE65-programmed BMDCs are recruited to the subretinal space, where they repopulate the RPE layer, preserve the photoreceptor layer, retain the thickness of the neural retina, reduce lipofuscin granule formation, and suppress microgliosis. Importantly, electroretinography and optokinetic response tests confirmed that visual function was significantly improved. Mice treated with non-modified BMDCs or BMDCs pre-programmed with LacZ did not exhibit significant improvement in visual deficit. RPE65-BMDC administration was most effective in early disease, when visual function and retinal morphology returned to near normal, and less effective in late-stage disease. This experimental paradigm offers a minimally invasive cellular therapy that can be given systemically overcoming the need for invasive ocular surgery and offering the potential to arrest progression in early AMD and other RPE-based diseases.
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Affiliation(s)
- Xiaoping Qi
- Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - S Louise Pay
- Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Yuanqing Yan
- Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA
| | - James Thomas
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA
| | - Alfred S Lewin
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA
| | - Lung-Ji Chang
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA
| | - Maria B Grant
- Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Michael E Boulton
- Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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Sok N, Baglin I, Basset C, Fakkor F, Kohli E, Rousselin Y, Bernhard C, Boschetti F, Goze C, Denat F. Straightforward synthesis of bis-tetraazacycloalkanes: towards new potential CXCR4 antagonists? RSC Adv 2017. [DOI: 10.1039/c7ra04218c] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
We report herein an efficient and general method for the synthesis of new bismacrocyclic compounds, structural analogues of biscyclam AMD3100, in which the two macrocycles are linked together through carbon atoms of the cycles.
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Affiliation(s)
- Nicolas Sok
- Univ. Bourgogne Franche-Comté
- AgroSup Dijon
- PAM UMR A 02.102
- F-21000 Dijon
- France
| | - Isabelle Baglin
- Institut de Chimie Moléculaire de l'Université de Bourgogne
- UMR CNRS 6302
- Univ. Bourgogne Franche-Comté
- 21078 Dijon Cedex
- France
| | - Christelle Basset
- INSERM UMR 866
- UFR des Sciences de Santé
- Univ. Bourgogne Franche-Comté
- Dijon
- France
| | | | - Evelyne Kohli
- INSERM UMR 866
- UFR des Sciences de Santé
- Univ. Bourgogne Franche-Comté
- Dijon
- France
| | - Yoann Rousselin
- Institut de Chimie Moléculaire de l'Université de Bourgogne
- UMR CNRS 6302
- Univ. Bourgogne Franche-Comté
- 21078 Dijon Cedex
- France
| | - Claire Bernhard
- Institut de Chimie Moléculaire de l'Université de Bourgogne
- UMR CNRS 6302
- Univ. Bourgogne Franche-Comté
- 21078 Dijon Cedex
- France
| | | | - Christine Goze
- Institut de Chimie Moléculaire de l'Université de Bourgogne
- UMR CNRS 6302
- Univ. Bourgogne Franche-Comté
- 21078 Dijon Cedex
- France
| | - Franck Denat
- Institut de Chimie Moléculaire de l'Université de Bourgogne
- UMR CNRS 6302
- Univ. Bourgogne Franche-Comté
- 21078 Dijon Cedex
- France
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Xiang Y, Pang BY, Zhang Y, Xie QL, Zhu Y, Leng AJ, Lu LQ, Chen HL. Effect of Yi Guan Jian decoction on differentiation of bone marrow mesenchymalstem cells into hepatocyte-like cells in dimethylnitrosamine-induced liver cirrhosis in mice. Mol Med Rep 2016; 15:613-626. [PMID: 28035356 PMCID: PMC5364852 DOI: 10.3892/mmr.2016.6083] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Accepted: 11/08/2016] [Indexed: 12/14/2022] Open
Abstract
Yi Guan Jian decoction (YGD) may induce the differentiation of bone marrow mesenchymal stem cells (BMSCs) into hepatocyte-like cells (HLCs); however, the underlying mechanisms remain to be elucidated. The present study aimed to investigate this process. To do this, a dimethylnitrosamine (DMN)-induced liver cirrhosis mouse model was established. The mice from the model group were randomly divided into three subgroups: i) Negative control, ii) hepatocyte growth factor and iii) YGD. The overall health, liver function and histological alterations were monitored. The expression of α‑smooth muscle actin (α‑SMA), C‑X‑C chemokine receptor type 4 (CXCR4), extracellular signal‑regulated kinase (ERK1/2), nuclear factor κB p65 subunit (NF‑κB p65) and β‑catenin were measured by immunohistochemistry, western blotting and reverse transcription‑quantitative polymerase chain reaction. Following administration of DMN, the overall health of the mice significantly decreased, with an increase in pathological developments and liver damage resulting in a decrease in liver function. Immunohistochemistry revealed that the expression of α‑SMA, CXCR4, ERK1/2, NF‑κB p65 and β‑catenin was upregulated. Following treatment with YGD, the overall health, liver function and pathology improved. The mRNA and protein expression levels of CXCR4 and ERK1/2 were upregulated, where as α‑SMA, NF‑κB p65 and β‑catenin levels were downregulated. The results demonstrated that YGD may induce the differentiation of BMSCs into HLCs to reverse DMN‑induced liver cirrhosis; this may be achieved via an upregulation of the SDF‑1/CXCR4 axis to activate the mitogen activated protein kinase/ERK1/2 signaling pathway.
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Affiliation(s)
- Yan Xiang
- Department of Infectious Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Bing-Yao Pang
- Department of Infectious Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Yuan Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Qiao-Ling Xie
- Department of Infectious Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Ying Zhu
- Department of Infectious Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Ai-Jing Leng
- Department of Pharmacy, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Long-Qing Lu
- Department of Infectious Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Hai-Long Chen
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
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Gaines T, Camp D, Bai R, Liang Z, Yoon Y, Shim H, Mooring SR. Synthesis and evaluation of 2,5 and 2,6 pyridine-based CXCR4 inhibitors. Bioorg Med Chem 2016; 24:5052-5060. [DOI: 10.1016/j.bmc.2016.08.018] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 08/08/2016] [Accepted: 08/12/2016] [Indexed: 12/13/2022]
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34
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Addington CP, Dharmawaj S, Heffernan JM, Sirianni RW, Stabenfeldt SE. Hyaluronic acid-laminin hydrogels increase neural stem cell transplant retention and migratory response to SDF-1α. Matrix Biol 2016; 60-61:206-216. [PMID: 27645115 DOI: 10.1016/j.matbio.2016.09.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2016] [Revised: 08/14/2016] [Accepted: 09/12/2016] [Indexed: 01/29/2023]
Abstract
The chemokine SDF-1α plays a critical role in mediating stem cell response to injury and disease and has specifically been shown to mobilize neural progenitor/stem cells (NPSCs) towards sites of neural injury. Current neural transplant paradigms within the brain suffer from low rates of retention and engraftment after injury. Therefore, increasing transplant sensitivity to injury-induced SDF-1α represents a method for increasing neural transplant efficacy. Previously, we have reported on a hyaluronic acid-laminin based hydrogel (HA-Lm gel) that increases NPSC expression of SDF-1α receptor, CXCR4, and subsequently, NPSC chemotactic migration towards a source of SDF-1α in vitro. The study presented here investigates the capacity of the HA-Lm gel to promote NPSC response to exogenous SDF-1α in vivo. We observed the HA-Lm gel to significantly increase NPSC transplant retention and migration in response to SDF-1α in a manner critically dependent on signaling via the SDF-1α-CXCR4 axis. This work lays the foundation for development of a more effective cell therapy for neural injury, but also has broader implications in the fields of tissue engineering and regenerative medicine given the essential roles of SDF-1α across injury and disease states.
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Affiliation(s)
- C P Addington
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, United States
| | - S Dharmawaj
- Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ, United States
| | - J M Heffernan
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, United States; Barrow Brain Tumor Research Center, Barrow Neurological Institute, Phoenix, AZ, United States
| | - R W Sirianni
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, United States; Barrow Brain Tumor Research Center, Barrow Neurological Institute, Phoenix, AZ, United States
| | - S E Stabenfeldt
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, United States.
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Molligan J, Mitchell R, Schon L, Achilefu S, Zahoor T, Cho Y, Loube J, Zhang Z. Influence of Bone and Muscle Injuries on the Osteogenic Potential of Muscle Progenitors: Contribution of Tissue Environment to Heterotopic Ossification. Stem Cells Transl Med 2016; 5:745-53. [PMID: 27112178 DOI: 10.5966/sctm.2015-0082] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Accepted: 02/15/2016] [Indexed: 12/17/2022] Open
Abstract
UNLABELLED : By using surgical mouse models, this study investigated how the tissue environment influences the osteogenic potential of muscle progenitors (m-progenitors) and potentially contributes to heterotopic ossification (HO). Injury was induced by clamping the gluteus maximus and medius (group M) or osteotomy of greater trochanter (group O) on the right hip, as well as combined muscle injury and osteotomy of greater trochanter (group M+O). The gluteus maximus and medius of the operated hips were harvested at days 1, 3, 5, and 10 for isolation of m-progenitors. The cells were cultured in an osteogenic medium for 3 weeks, and osteogenesis was evaluated by matrix mineralization and the expression of osteogenesis-related genes. The expression of type I collagen, RUNX2 (runt-related transcription factor 2), and osteocalcin by the m-progenitors of group M+O was significantly increased, compared with groups M and O. Osteogenic m-progenitors in group O increased the expression of bone morphogenetic protein 2 and also bone morphogenetic protein antagonist differential screening-selected gene aberrative in neuroblastoma. On histology, there was calcium deposition mostly in the muscles of group M+O harvested at day 10. CD56, representing myogenic progenitors, was highly expressed in the m-progenitors isolated from group M (day 10), but m-progenitors of group M+O (day 10) exhibited the highest expression of platelet-derived growth factor receptor α (PDGFR-α), a marker of muscle-derived mesenchymal stem cells (M-MSCs). The expressions of PDGFR-α and RUNX2 were colocalized in osteogenic m-progenitors. The data indicate that the tissue environment simulated in the M+O model is a favorable condition for HO formation. Most likely, M-MSCs, rather than myogenic progenitors, in the m-progenitors participate in HO formation. SIGNIFICANCE The prevalence of traumatic heterotopic ossification (HO) is high in war injury. The pathogenesis of HO is still unknown. This study clarified the contribution of a tissue environment created by bone or muscle injury to the formation of HO. The study also found that muscle-derived mesenchymal stem cells, but not myogenic progenitors, are involved in the formation of HO. The findings of this study could be used to strategize the prevention and treatment of HO.
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Affiliation(s)
- Jeremy Molligan
- Orthobiologic Laboratory, MedStar Union Memorial Hospital, Baltimore, Maryland, USA
| | - Reed Mitchell
- Orthobiologic Laboratory, MedStar Union Memorial Hospital, Baltimore, Maryland, USA
| | - Lew Schon
- Orthobiologic Laboratory, MedStar Union Memorial Hospital, Baltimore, Maryland, USA
| | - Samuel Achilefu
- Department of Radiology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Talal Zahoor
- Orthobiologic Laboratory, MedStar Union Memorial Hospital, Baltimore, Maryland, USA
| | - Young Cho
- Orthobiologic Laboratory, MedStar Union Memorial Hospital, Baltimore, Maryland, USA
| | - Jeffery Loube
- Orthobiologic Laboratory, MedStar Union Memorial Hospital, Baltimore, Maryland, USA
| | - Zijun Zhang
- Orthobiologic Laboratory, MedStar Union Memorial Hospital, Baltimore, Maryland, USA
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Guided bone regeneration is promoted by the molecular events in the membrane compartment. Biomaterials 2016; 84:167-183. [DOI: 10.1016/j.biomaterials.2016.01.034] [Citation(s) in RCA: 113] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 01/18/2016] [Indexed: 11/18/2022]
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Elgali I, Turri A, Xia W, Norlindh B, Johansson A, Dahlin C, Thomsen P, Omar O. Guided bone regeneration using resorbable membrane and different bone substitutes: Early histological and molecular events. Acta Biomater 2016; 29:409-423. [PMID: 26441123 DOI: 10.1016/j.actbio.2015.10.005] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Revised: 09/03/2015] [Accepted: 10/02/2015] [Indexed: 11/26/2022]
Abstract
Bone insufficiency remains a major challenge for bone-anchored implants. The combination of guided bone regeneration (GBR) and bone augmentation is an established procedure to restore the bone. However, a proper understanding of the interactions between the bone substitute and GBR membrane materials and the bone-healing environment is lacking. This study aimed to investigate the early events of bone healing and the cellular activities in response to a combination of GBR membrane and different calcium phosphate (CaP) materials. Defects were created in the trabecular region of rat femurs, and filled with deproteinized bovine bone (DBB), hydroxyapatite (HA) or strontium-doped HA (SrHA) or left empty (sham). All the defects were covered with an extracellular matrix membrane. Defects were harvested after 12h, 3d and 6d for histology/histomorphometry, immunohistochemistry and gene expression analyses. Histology revealed new bone, at 6d, in all the defects. Larger amount of bone was observed in the SrHA-filled defect. This was in parallel with the reduced expression of osteoclastic genes (CR and CatK) and the osteoblast-osteoclast coupling gene (RANKL) in the SrHA defects. Immunohistochemistry indicated fewer osteoclasts in the SrHA defects. The observations of CD68 and periostin-expressing cells in the membrane per se indicated that the membrane may contribute to the healing process in the defect. It is concluded that the bone-promoting effects of Sr in vivo are mediated by a reduction in catabolic and osteoblast-osteoclast coupling processes. The combination of a bioactive membrane and CaP bone substitute material doped with Sr may produce early synergistic effects during GBR. STATEMENT OF SIGNIFICANCE The study provides novel molecular, cellular and structural evidence on the promotion of early bone regeneration in response to synthetic strontium-containing hydroxyapatite (SrHA) substitute, in combination with a resorbable, guided bone regeneration (GBR) membrane. The prevailing view, based mainly upon in vitro data, is that the beneficial effects of Sr are exerted by the stimulation of bone-forming cells (osteoblasts) and the inhibition of bone-resorbing cells (osteoclasts). In contrast, the present study demonstrates that the local effect of Sr in vivo is predominantly via the inhibition of osteoclast number and activity and the reduction of osteoblast-osteoclast coupling. This experimental data will form the basis for clinical studies, using this material as an interesting bone substitute for guided bone regeneration.
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Pathological Left Ventricular Hypertrophy and Stem Cells: Current Evidence and New Perspectives. Stem Cells Int 2015; 2016:5720758. [PMID: 26798360 PMCID: PMC4699040 DOI: 10.1155/2016/5720758] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 08/17/2015] [Accepted: 09/06/2015] [Indexed: 12/17/2022] Open
Abstract
Left ventricular hypertrophy (LVH) is a strong predictor of adverse cardiovascular outcomes. It is the result of complex mechanisms that include not only an increase in protein synthesis and cell size but also proliferating cardiac progenitor cells and the influx of bone marrow-derived cells developing into cardiomyocytes. Stem and progenitor cells are known to contribute to the renewal of adult mammalian cardiomyocytes in case of myocardial injury or pressure and volume overload. They are activated in LVH and play a regulatory role in myocardial repair. They have high proliferative potential and secrete numerous cytokines, growth factors, and microRNAs that play important roles in cell differentiation, cardiac remodeling, and neovascularization. They are mobilized in response to either mechanical or chemical stimuli, hormones, or pharmacologic agents. Another important source of progenitor cells is the epicardial layer. It appears that precursor cells migrate from the epicardium to the myocardium in order to interact with myocardial cells. In addition, migratory cells participate in the formation of almost all cardiac structures in myocardial hypertrophy. Although the pathophysiological mechanisms are still obscure and further studies are required, their properties may open the door to regenerative cell therapy for the prevention of adverse remodeling.
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Stem Cell-Based Therapeutics to Improve Wound Healing. PLASTIC SURGERY INTERNATIONAL 2015; 2015:383581. [PMID: 26649195 PMCID: PMC4663003 DOI: 10.1155/2015/383581] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Revised: 10/13/2015] [Accepted: 10/15/2015] [Indexed: 12/18/2022]
Abstract
Issues surrounding wound healing have garnered deep scientific interest as well as booming financial markets invested in novel wound therapies. Much progress has been made in the field, but it is unsurprising to find that recent successes reveal new challenges to be addressed. With regard to wound healing, large tissue deficits, recalcitrant wounds, and pathological scar formation remain but a few of our most pressing challenges. Stem cell-based therapies have been heralded as a promising means by which to surpass current limitations in wound management. The wide differentiation potential of stem cells allows for the possibility of restoring lost or damaged tissue, while their ability to immunomodulate the wound bed from afar suggests that their clinical applications need not be restricted to direct tissue formation. The clinical utility of stem cells has been demonstrated across dozens of clinical trials in chronic wound therapy, but there is hope that other aspects of wound care will inherit similar benefit. Scientific inquiry into stem cell-based wound therapy abounds in research labs around the world. While their clinical applications remain in their infancy, the heavy investment in their potential makes it a worthwhile subject to review for plastic surgeons, in terms of both their current and future applications.
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Effective Mobilization of Very Small Embryonic-Like Stem Cells and Hematopoietic Stem/Progenitor Cells but Not Endothelial Progenitor Cells by Follicle-Stimulating Hormone Therapy. Stem Cells Int 2015; 2016:8530207. [PMID: 26635885 PMCID: PMC4655290 DOI: 10.1155/2016/8530207] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Accepted: 06/08/2015] [Indexed: 12/17/2022] Open
Abstract
Recently, murine hematopoietic progenitor stem cells (HSCs) and very small embryonic-like stem cells (VSELs) were demonstrated to express receptors for sex hormones including follicle-stimulating hormone (FSH). This raised the question of whether FSH therapy at clinically applied doses can mobilize stem/progenitor cells in humans. Here we assessed frequencies of VSELs (referred to as Lin−CD235a−CD45−CD133+ cells), HSPCs (referred to as Lin−CD235a−CD45+CD133+ cells), and endothelial progenitor cells (EPCs, identified as CD34+CD144+, CD34+CD133+, and CD34+CD309+CD133+ cells) in fifteen female patients subjected to the FSH therapy. We demonstrated that FSH therapy resulted in statistically significant enhancement in peripheral blood (PB) number of both VSELs and HSPCs. In contrast, the pattern of responses of EPCs delineated by different cell phenotypes was not uniform and we did not observe any significant changes in EPC numbers following hormone therapy. Our data indicate that FSH therapy mobilizes VSELs and HSPCs into peripheral blood that on one hand supports their developmental origin from germ lineage, and on the other hand FSH can become a promising candidate tool for mobilizing HSCs and stem cells with VSEL phenotype in clinical settings.
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Rutten MJ, Laraway B, Gregory CR, Xie H, Renken C, Keese C, Gregory KW. Rapid assay of stem cell functionality and potency using electric cell-substrate impedance sensing. Stem Cell Res Ther 2015; 6:192. [PMID: 26438432 PMCID: PMC4594964 DOI: 10.1186/s13287-015-0182-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 07/30/2015] [Accepted: 09/10/2015] [Indexed: 01/09/2023] Open
Abstract
Regenerative medicine studies using autologous bone marrow mononuclear cells (BM-MNCs) have shown improved clinical outcomes that correlate to in vitro BM-MNC invasive capacity. The current Boyden-chamber assay for testing invasive capacity is labor-intensive, provides only a single time point, and takes 36 hours to collect data and results, which is not practical from a clinical cell delivery perspective. To develop a rapid, sensitive and reproducible invasion assay, we employed Electric Cell-substrate Impedance Sensing (ECIS) technology. Chemokine-directed BM-MNC cell invasion across a Matrigel-coated Transwell filter was measurable within minutes using the ECIS system we developed. This ECIS-Transwell chamber system provides a rapid and sensitive test of stem and progenitor cell invasive capacity for evaluation of stem cell functionality to provide timely clinical data for selection of patients likely to realize clinical benefit in regenerative medicine treatments. This device could also supply robust unambiguous, reproducible and cost effective data as a potency assay for cell product release and regulatory strategies.
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Affiliation(s)
- Michael J Rutten
- Center for Regenerative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, 97239, Portland, OR, USA.
| | - Bryan Laraway
- Center for Regenerative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, 97239, Portland, OR, USA.
| | - Cynthia R Gregory
- Center for Regenerative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, 97239, Portland, OR, USA. .,VA Portland Health Care System, 3710 SW US Veterans Hospital Road, 97239, Portland, OR, USA. .,Department of Molecular Microbiology and Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, 97239, Portland, OR, USA.
| | - Hua Xie
- Center for Regenerative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, 97239, Portland, OR, USA.
| | - Christian Renken
- Applied BioPhysics, Inc., 185 Jordan Road, 12180, Troy, NY, USA.
| | - Charles Keese
- Applied BioPhysics, Inc., 185 Jordan Road, 12180, Troy, NY, USA.
| | - Kenton W Gregory
- Center for Regenerative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, 97239, Portland, OR, USA. .,Department of Biomedical Engineering, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, 97239, Portland, OR, USA.
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Godoy JA, Carneiro GD, Sielski MS, Barbosa GO, Werneck CC, Vicente CP. Combined dermatan sulfate and endothelial progenitor cell treatment: action on the initial inflammatory response after arterial injury in C57BL/6 mice. Cytotherapy 2015; 17:1447-64. [DOI: 10.1016/j.jcyt.2015.07.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 07/03/2015] [Accepted: 07/05/2015] [Indexed: 01/23/2023]
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A comparison of stromal cell-derived factor-1 expression during distraction osteogenesis and bone fracture in the mandible. J Craniofac Surg 2015; 24:805-8. [PMID: 23714884 DOI: 10.1097/scs.0b013e31828f1ca7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Distraction osteogenesis (DO) has been a widely applied technique in orthopedics and craniofacial surgery. However, the exact molecular mechanism by which the mechanical stimulus is translated into biological signals is still poorly understood. In this study, we examined and compared the expression of stromal cell-derived factor-1 (SDF-1) during mandibular distraction osteogenesis and fracture in rats, respectively. Forty-eight male Sprague-Dawley rats were divided into 2 groups and received unilateral distraction osteogenesis and rigid internal fixation, respectively, after the osteotomy on the right mandible. The harvested mandibles were examined radiographically, histologically, and immunohistochemically. We found that the expression of SDF-1 was mainly detected in the osteoblasts and blood vessels, and there were more intensive expression of SDF-1 in DO zones than in bone fracture zones. The quantitative analysis by enzyme-linked immunosorbent assay showed that SDF-1 reached a greater peak and maintained a longer period of up-regulation in DO than in fracture healing (P < 0.05). These results suggest that the distraction procedure markedly promotes the high expression of SDF-1 which facilitates the induction of bone formation during DO.
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Thulasitha WS, Umasuthan N, Whang I, Lim BS, Jung HB, Noh JK, Lee J. A CXC chemokine gene, CXCL12, from rock bream, Oplegnathus fasciatus: Molecular characterization and transcriptional profile. FISH & SHELLFISH IMMUNOLOGY 2015; 45:560-566. [PMID: 25979602 DOI: 10.1016/j.fsi.2015.05.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Revised: 04/29/2015] [Accepted: 05/04/2015] [Indexed: 06/04/2023]
Abstract
Chemokines are small, structurally related chemotactic cytokines characterized by the presence of conserved cysteine residues. In the present study, we identified the cDNA of a CXC chemokine from Oplegnathus fasciatus, designated as OfCXCL12. An open reading frame of 297 bp encoded a 98 amino acid peptide with a putative signal peptide of 23 amino acids. The CXC family-specific small cytokine domain (SCY), which is highly conserved among vertebrates, was located between residues 29 and 87. The characteristic conserved cysteine residues in the CXC motif of OfCXCL12 were separated by tyrosine (Y). Similar to other vertebrate CXCL12 proteins, OfCXCL12 also lacked the ELR motif and hence belongs to ELR(-) subfamily. Phylogenetic analysis revealed two distinct clades, consisting of fish and tetrapod CXCL12 homologs. Constitutive expression with significantly higher levels of OfCXCL12 mRNA transcription was detected in immune-related organs, including the head kidney, spleen, and kidney. Infection with bacterial and viral agents led to significant upregulation of mRNA expression in both the head kidney and spleen, in a stimulant-specific manner. Stimulation of peripheral blood leukocytes by the mitogen concanavalin-A significantly induced OfCXCL12 transcription. Results from the present study suggest an important role for OfCXCL12 in immune defense against bacterial and viral infection in rock bream.
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Affiliation(s)
- William Shanthakumar Thulasitha
- Department of Marine Life Sciences, School of Marine Biomedical Sciences, Jeju National University, Jeju Self-Governing Province 690-756, Republic of Korea; Fish Vaccine Development Center, Jeju National University, Jeju Self-Governing Province 690-756, Republic of Korea
| | - Navaneethaiyer Umasuthan
- Department of Marine Life Sciences, School of Marine Biomedical Sciences, Jeju National University, Jeju Self-Governing Province 690-756, Republic of Korea; Fish Vaccine Development Center, Jeju National University, Jeju Self-Governing Province 690-756, Republic of Korea
| | - Ilson Whang
- Fish Vaccine Development Center, Jeju National University, Jeju Self-Governing Province 690-756, Republic of Korea
| | - Bong-Soo Lim
- Fish Vaccine Development Center, Jeju National University, Jeju Self-Governing Province 690-756, Republic of Korea
| | - Hyung-Bok Jung
- Fish Vaccine Development Center, Jeju National University, Jeju Self-Governing Province 690-756, Republic of Korea
| | - Jae Koo Noh
- Genetics & Breeding Research Center, National Fisheries Research & Development Institute, Geoje 656-842, Republic of Korea
| | - Jehee Lee
- Department of Marine Life Sciences, School of Marine Biomedical Sciences, Jeju National University, Jeju Self-Governing Province 690-756, Republic of Korea; Fish Vaccine Development Center, Jeju National University, Jeju Self-Governing Province 690-756, Republic of Korea.
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45
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The effect of stromal cell-derived factor 1 in the migration of neural stem cells. Cell Biochem Biophys 2015; 70:1609-16. [PMID: 25241080 DOI: 10.1007/s12013-014-0103-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Neural stem cells (NSCs) have widely been used in the treatment of human neurological disorders as cell therapy via intracerebral or intraventricular infusion. However, the migration mechanism required for NSCs homing and recruitment remains to be elucidated. Recently, SDF-1/CXCR4 axis was shown to be responsible for in cell migration and differentiation during the neural development stage and involved in the pathophysiological process of neurological disorders. In this study, we investigated the effect of SDF-1 in migration of NSCs in vitro and in vivo. The expression of CXCR4 receptor was examined by immunocytochemistry and RT-PCR. The migratory ability of NSCs induced by SDF-1 was assessed by transwell chemotaxis assay. The traumatic brain injury rat model was well established, and the recruitment of NSCs and expression of SDF-1 were investigated in vivo. Our findings demonstrated that SDF-1, in vitro, significantly induced the migratory of NSCs in a dose-dependent manner. An overexpression of neural stem cell marker Nestin in the hippocampus was observed after TBI, and the expressions of SDF-1 surrounding the lesion areas were significantly increased. Our results suggested that the migration of NSCs was activated by chemotactic effect of SDF-1. It was also proved the relevance of SDF-1 in the migration of endogenous NSCs after brain injury. Taken together, these results demonstrated that SDF-1/CXCR4 axis may play crucial role in the migration of Nestin-positive cell after brain injury.
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Akazawa Y, Hasegawa T, Yoshimura Y, Chosa N, Asakawa T, Ueda K, Sugimoto A, Kitamura T, Nakagawa H, Ishisaki A, Iwamoto T. Recruitment of mesenchymal stem cells by stromal cell-derived factor 1α in pulp cells from deciduous teeth. Int J Mol Med 2015; 36:442-8. [PMID: 26082290 DOI: 10.3892/ijmm.2015.2247] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 05/19/2015] [Indexed: 12/19/2022] Open
Abstract
Dental pulp cells (DPCs), including dental pulp (DP) stem cells, play a role in dentine repair under certain conditions caused by bacterial infections associated with caries, tooth fracture and injury. Mesenchymal stem cells (MSCs) have also been shown to be involved in this process of repair. However, the mechanisms through which MSCs are recruited to the DP have not yet been elucidated. Therefore, the aim of the present in vitro study was to investigate whether stromal cell-derived factor 1α (SDF1)-C-X-C chemokine receptor type 4 (CXCR4) signaling is involved in tissue repair in the DP of deciduous teeth. A single-cell clone from DPCs (SDP11) and UE7T-13 cells were used as pulp cells and MSCs, respectively. The MG-63 and HuO9 cells, two osteosarcoma cell lines, were used as positive control cells. Reverse transcription polymerase chain reaction (RT-PCR) revealed that all cell lines (SDP11, UE7T-13 MG-63 and HuO9) were positive for both SDF1 and CXCR4 mRNA expression. Moreover, immunocytochemical analysis indicated that SDF1 and CXCR4 proteins were expressed in the SDP11 and UE7T-13 cells. SDF1 was also detected in the cell lysates (CLs) and conditioned medium (CM) collected from the SDP11 and UE7T-13 cells, and AMD3100, a specific antagonist of CXCR4, inhibited the migration of the UE7T-13 cells; this migration was induced by treatment with CM, which was collected from the SDP11 cells. In addition, real-time PCR showed that the expression of SDF1 in the SDP11 cells was inhibited by treatment with 20 ng/ml fibroblast growth factor (FGF)-2, and exposure to AZD4547, an inhibitor of the FGF receptor, blocked this inhibition. Collectively, these data suggest that SDF1 produced by DP plays an important role in homeostasis, repair and regeneration via the recruitment of MSCs.
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Affiliation(s)
- Yuki Akazawa
- Department of Pediatric Dentistry, Tokushima University Hospital, Tokushima 770‑8504, Japan
| | - Tomokazu Hasegawa
- Department of Pediatric Dentistry, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770‑8504, Japan
| | - Yoshitaka Yoshimura
- Department of Molecular Cell Pharmacology, Division of Oral Pathological Science, Hokkaido University Graduate School of Dental Medicine, Sapporo, Hokkaido 060-8586, Japan
| | - Naoyuki Chosa
- Department of Oral Biochemistry, School of Dentistry, Iwate Medical University, Morioka, Iwate 020-8505, Japan
| | - Takeyoshi Asakawa
- Department of Special Needs Dentistry, Division of Dentistry for Persons with Disabilities, Showa University School of Dentistry, Tokyo 145-8515, Japan
| | - Kimiko Ueda
- Department of Pediatric Dentistry, Tokushima University Hospital, Tokushima 770‑8504, Japan
| | - Asuna Sugimoto
- Department of Pediatric Dentistry, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770‑8504, Japan
| | - Takamasa Kitamura
- Department of Pediatric Dentistry, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770‑8504, Japan
| | - Hiroshi Nakagawa
- Department of Pediatric Dentistry, Tokushima University Hospital, Tokushima 770‑8504, Japan
| | - Akira Ishisaki
- Department of Oral Biochemistry, School of Dentistry, Iwate Medical University, Morioka, Iwate 020-8505, Japan
| | - Tsutomu Iwamoto
- Department of Pediatric Dentistry, Tokushima University Hospital, Tokushima 770‑8504, Japan
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EXP CLIN TRANSPLANTExp Clin Transplant 2015; 13. [DOI: 10.6002/ect.2014.0216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
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Maguire G, Friedman P. Systems biology approach to developing S 2RM-based “systems therapeutics” and naturally induced pluripotent stem cells. World J Stem Cells 2015; 7:745-756. [PMID: 26029345 PMCID: PMC4444614 DOI: 10.4252/wjsc.v7.i4.745] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 11/25/2014] [Accepted: 03/18/2015] [Indexed: 02/06/2023] Open
Abstract
The degree to, and the mechanisms through, which stem cells are able to build, maintain, and heal the body have only recently begun to be understood. Much of the stem cell’s power resides in the release of a multitude of molecules, called stem cell released molecules (SRM). A fundamentally new type of therapeutic, namely “systems therapeutic”, can be realized by reverse engineering the mechanisms of the SRM processes. Recent data demonstrates that the composition of the SRM is different for each type of stem cell, as well as for different states of each cell type. Although systems biology has been successfully used to analyze multiple pathways, the approach is often used to develop a small molecule interacting at only one pathway in the system. A new model is emerging in biology where systems biology is used to develop a new technology acting at multiple pathways called “systems therapeutics”. A natural set of healing pathways in the human that uses SRM is instructive and of practical use in developing systems therapeutics. Endogenous SRM processes in the human body use a combination of SRM from two or more stem cell types, designated as S2RM, doing so under various state dependent conditions for each cell type. Here we describe our approach in using state-dependent SRM from two or more stem cell types, S2RM technology, to develop a new class of therapeutics called “systems therapeutics.” Given the ubiquitous and powerful nature of innate S2RM-based healing in the human body, this “systems therapeutic” approach using S2RM technology will be important for the development of anti-cancer therapeutics, antimicrobials, wound care products and procedures, and a number of other therapeutics for many indications.
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Kaku M, Akiba Y, Akiyama K, Akita D, Nishimura M. Cell-based bone regeneration for alveolar ridge augmentation--cell source, endogenous cell recruitment and immunomodulatory function. J Prosthodont Res 2015; 59:96-112. [PMID: 25749435 DOI: 10.1016/j.jpor.2015.02.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 02/05/2015] [Indexed: 11/30/2022]
Abstract
Alveolar ridge plays a pivotal role in supporting dental prosthesis particularly in edentulous and semi-dentulous patients. However the alveolar ridge undergoes atrophic change after tooth loss. The vertical and horizontal volume of the alveolar ridge restricts the design of dental prosthesis; thus, maintaining sufficient alveolar ridge volume is vital for successful oral rehabilitation. Recent progress in regenerative approaches has conferred marked benefits in prosthetic dentistry, enabling regeneration of the atrophic alveolar ridge. In order to achieve successful alveolar ridge augmentation, sufficient numbers of osteogenic cells are necessary; therefore, autologous osteoprogenitor cells are isolated, expanded in vitro, and transplanted to the specific anatomical site where the bone is required. Recent studies have gradually elucidated that transplanted osteoprogenitor cells are not only a source of bone forming osteoblasts, they appear to play multiple roles, such as recruitment of endogenous osteoprogenitor cells and immunomodulatory function, at the forefront of bone regeneration. This review focuses on the current consensus of cell-based bone augmentation therapies with emphasis on cell sources, transplanted cell survival, endogenous stem cell recruitment and immunomodulatory function of transplanted osteoprogenitor cells. Furthermore, if we were able to control the mobilization of endogenous osteoprogenitor cells, large-scale surgery may no longer be necessary. Such treatment strategy may open a new era of safer and more effective alveolar ridge augmentation treatment options.
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Affiliation(s)
- Masaru Kaku
- Division of Bioprosthodontics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
| | - Yosuke Akiba
- Division of Bioprosthodontics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kentaro Akiyama
- Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Daisuke Akita
- Department of Partial Denture Prosthodontics, Nihon University School of Dentistry, Tokyo, Japan
| | - Masahiro Nishimura
- Department of Oral Maxillofacial Prosthodontics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
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Wang J, Liu X, Lu H, Jiang C, Cui X, Yu L, Fu X, Li Q, Wang J. CXCR4(+)CD45(-) BMMNC subpopulation is superior to unfractionated BMMNCs for protection after ischemic stroke in mice. Brain Behav Immun 2015; 45:98-108. [PMID: 25526817 PMCID: PMC4342301 DOI: 10.1016/j.bbi.2014.12.015] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Revised: 12/05/2014] [Accepted: 12/10/2014] [Indexed: 02/07/2023] Open
Abstract
Cell-based therapy is considered to be a promising therapeutic strategy for stroke treatment. Although unfractionated bone marrow mononuclear cells (BMMNCs) have been tried in both preclinical and clinical trials, the effective subpopulations need to be identified. In this study, we used fluorescence-activated cell sorting to harvest the CXCR4(+)CD45(+) and CXCR4(+)CD45(-) BMMNC subpopulations from transgenic mice that express enhanced green fluorescent protein. We then allogeneically grafted unfractionated BMMNCs or a subpopulation into mice subjected to transient middle cerebral artery occlusion (tMCAO) and compared the effects on stroke outcomes. We found that CXCR4(+)CD45(-) BMMNCs, but not CXCR4(+)CD45(+) BMMNCs, more effectively reduced infarction volume and neurologic deficits than did unfractionated BMMNCs. Brain tissue from the ischemic hemisphere of mice treated with CXCR4(+)CD45(-) BMMNCs had higher levels of vascular endothelial growth factor and lower levels of TNF-α than did tissue from mice treated with unfractionated BMMNCs. In contrast, CXCR4(+)CD45(+) BMMNCs showed an increase in TNF-α. Additionally, CXCR4(+)CD45(+) and CXCR4(+)CD45(-) populations exhibited more robust migration into the lesion areas and were better able to express cell-specific markers of different linages than were the unfractionated BMMNCs. Endothelial and astrocyte cell markers did not colocalize with eGFP(+) cells in the brains of tMCAO mice that received CXCR4(+)CD45(+) BMMNCs. In vitro, the CXCR4(+)CD45(-) BMMNCs expressed significantly more Oct-4 and Nanog mRNA than did the unfractionated BMMNCs. However, we did not detect gene expression of these two pluripotent markers in CXCR4(+)CD45(+) BMMNCs. Taken together, our study shows for the first time that the CXCR4(+)CD45(-) BMMNC subpopulation is superior to unfractionated BMMNCs in ameliorating cerebral damage in a mouse model of tMCAO and could represent a new therapeutic approach for stroke treatment.
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Affiliation(s)
- Jianping Wang
- Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
| | - Xi Liu
- Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Hong Lu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China
| | - Chao Jiang
- Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China,Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Xiaobing Cui
- Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Lie Yu
- Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Xiaojie Fu
- Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Qian Li
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Jian Wang
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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