Stem cells translational medicine
2157-6564
2157-6580
Mỹ
Cơ quản chủ quản: OXFORD UNIV PRESS , Oxford University Press
Lĩnh vực:
Developmental BiologyCell BiologyMedicine (miscellaneous)
Các bài báo tiêu biểu
Concise Review: Role of Mesenchymal Stem Cells in Wound Repair Abstract Wound healing requires a coordinated interplay among cells, growth factors, and extracellular matrix proteins. Central to this process is the endogenous mesenchymal stem cell (MSC), which coordinates the repair response by recruiting other host cells and secreting growth factors and matrix proteins. MSCs are self-renewing multipotent stem cells that can differentiate into various lineages of mesenchymal origin such as bone, cartilage, tendon, and fat. In addition to multilineage differentiation capacity, MSCs regulate immune response and inflammation and possess powerful tissue protective and reparative mechanisms, making these cells attractive for treatment of different diseases. The beneficial effect of exogenous MSCs on wound healing was observed in a variety of animal models and in reported clinical cases. Specifically, they have been successfully used to treat chronic wounds and stimulate stalled healing processes. Recent studies revealed that human placental membranes are a rich source of MSCs for tissue regeneration and repair. This review provides a concise summary of current knowledge of biological properties of MSCs and describes the use of MSCs for wound healing. In particular, the scope of this review focuses on the role MSCs have in each phase of the wound-healing process. In addition, characterization of MSCs containing skin substitutes is described, demonstrating the presence of key growth factors and cytokines uniquely suited to aid in wound repair.
Tập 1 Số 2 - Trang 142-149 - 2012
Các túi ngoại tiết cải thiện tái sinh thần kinh sau đột quỵ và ngăn ngừa suy giảm miễn dịch sau thiếu máu cục bộ Tóm tắt
Mặc dù các khái niệm ban đầu về liệu pháp tế bào gốc nhằm thay thế mô bị mất, nhưng bằng chứng gần đây đã gợi ý rằng cả tế bào gốc và tiền thân đều thúc đẩy phục hồi thần kinh sau thiếu máu cục bộ thông qua các yếu tố tiết ra giúp phục hồi khả năng tái cấu trúc của não bị tổn thương. Cụ thể, các túi ngoại tiết (EVs) từ các tế bào gốc như exosomes đã được đề xuất gần đây có vai trò trung gian cho các tác dụng phục hồi của tế bào gốc. Để xác định liệu EVs có thực sự cải thiện suy giảm thần kinh sau thiếu máu cục bộ và tái cấu trúc não hay không, chúng tôi đã so sánh có hệ thống các tác động của các túi ngoại tiết (MSC-EVs) từ tế bào gốc trung mô (MSCs) so với MSCs được truyền i.v. vào chuột trong các ngày 1, 3 và 5 (MSC-EVs) hoặc ngày 1 (MSCs) sau khi xảy ra thiếu máu cục bộ não tiêu điểm ở chuột C57BL6. Trong 28 ngày sau khi đột quỵ, các điểm yếu về phối hợp vận động, tổn thương não trên mô học, phản ứng miễn dịch trong máu ngoại vi và não, cùng những thay đổi về tạo mạch và sinh trưởng tâm thần kinh đã được phân tích. Cải thiện suy giảm thần kinh và bảo vệ thần kinh dài hạn kết hợp với tăng cường tạo mạch thần kinh và thần kinh đã được ghi nhận ở các con chuột bị đột quỵ nhận EVs từ hai dòng MSC nguồn gốc tủy xương khác nhau. Việc sử dụng MSC-EV mô phỏng chính xác các phản ứng của MSCs và kéo dài suốt giai đoạn quan sát. Mặc dù sự xâm nhập của tế bào miễn dịch não không bị ảnh hưởng bởi MSC-EVs, sự suy giảm miễn dịch sau thiếu máu cục bộ (tức là B-cell, tế bào giết tự nhiên và lymphopenia tế bào T) đã giảm bớt trong máu ngoại vi ở 6 ngày sau thiếu máu cục bộ, cung cấp môi trường ngoại vi thích hợp cho tái cấu trúc não thành công. Vì các nghiên cứu gần đây cho thấy MSC-EVs an toàn với con người, nghiên cứu này cung cấp bằng chứng lâm sàng quan trọng cần thiết cho các nghiên cứu chứng minh nhanh chóng trong bệnh nhân đột quỵ.
Ý nghĩa
Cấy ghép các tế bào gốc trung mô (MSCs) cung cấp một phương pháp tiếp cận hỗ trợ quan trọng bên cạnh việc làm tan cục máu đông để điều trị đột quỵ thiếu máu cục bộ. Tuy nhiên, MSCs không tích hợp vào các mạng lưới thần kinh cư trú mà hoạt động gián tiếp, gây bảo vệ thần kinh và thúc đẩy tái sinh thần kinh. Mặc dù cơ chế MSCs hoạt động còn chưa rõ ràng, bằng chứng gần đây đã gợi ý rằng các túi ngoại tiết (EVs) có thể chịu trách nhiệm cho các tác dụng gây ra bởi MSCs dưới điều kiện sinh lý và bệnh lý. Nghiên cứu hiện tại đã chứng minh rằng EVs không thua kém MSCs trong mô hình đột quỵ động vật gặm nhấm. EVs gây bảo vệ thần kinh lâu dài, thúc đẩy tái sinh thần kinh và phục hồi chức năng thần kinh, và điều tiết các phản ứng miễn dịch sau đột quỵ ngoại biên. Ngoài ra, vì EVs dung nạp tốt ở người theo báo cáo trước đó, việc sử dụng EVs trong điều kiện lâm sàng có thể mở đường cho một định nghĩa điều trị đột quỵ mới và sáng tạo mà không có các tác dụng phụ dự kiến liên quan đến cấy ghép tế bào gốc.
Tập 4 Số 10 - Trang 1131-1143 - 2015
#EVs #tế bào gốc trung mô #thiếu máu cục bộ #tái sinh thần kinh #bảo vệ thần kinh #miễn dịch học #đột quỵ #exosomes #tái cấu trúc não #tổn thương não
Concise Review: Multifaceted Characterization of Human Mesenchymal Stem Cells for Use in Regenerative Medicine Abstract Mesenchymal stem cells (MSC) hold great potential for regenerative medicine because of their ability for self-renewal and differentiation into tissue-specific cells such as osteoblasts, chondrocytes, and adipocytes. MSCs orchestrate tissue development, maintenance and repair, and are useful for musculoskeletal regenerative therapies to treat age-related orthopedic degenerative diseases and other clinical conditions. Importantly, MSCs produce secretory factors that play critical roles in tissue repair that support both engraftment and trophic functions (autocrine and paracrine). The development of uniform protocols for both preparation and characterization of MSCs, including standardized functional assays for evaluation of their biological potential, are critical factors contributing to their clinical utility. Quality control and release criteria for MSCs should include cell surface markers, differentiation potential, and other essential cell parameters. For example, cell surface marker profiles (surfactome), bone-forming capacities in ectopic and orthotopic models, as well as cell size and granularity, telomere length, senescence status, trophic factor secretion (secretome), and immunomodulation, should be thoroughly assessed to predict MSC utility for regenerative medicine. We propose that these and other functionalities of MSCs should be characterized prior to use in clinical applications as part of comprehensive and uniform guidelines and release criteria for their clinical-grade production to achieve predictably favorable treatment outcomes for stem cell therapy.
Tập 6 Số 12 - Trang 2173-2185 - 2017
Cartilage Regeneration in Osteoarthritic Patients by a Composite of Allogeneic Umbilical Cord Blood-Derived Mesenchymal Stem Cells and Hyaluronate Hydrogel: Results from a Clinical Trial for Safety and Proof-of-Concept with 7 Years of Extended Follow-Up Abstract
Few methods are available to regenerate articular cartilage defects in patients with osteoarthritis. We aimed to assess the safety and efficacy of articular cartilage regeneration by a novel medicinal product composed of allogeneic human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs). Patients with Kellgren-Lawrence grade 3 osteoarthritis and International Cartilage Repair Society (ICRS) grade 4 cartilage defects were enrolled in this clinical trial. The stem cell-based medicinal product (a composite of culture-expanded allogeneic hUCB-MSCs and hyaluronic acid hydrogel [Cartistem]) was applied to the lesion site. Safety was assessed by the World Health Organization common toxicity criteria. The primary efficacy outcome was ICRS cartilage repair assessed by arthroscopy at 12 weeks. The secondary efficacy outcome was visual analog scale (VAS) score for pain on walking. During a 7-year extended follow-up, we evaluated safety, VAS score, International Knee Documentation Committee (IKDC) subjective score, magnetic resonance imaging (MRI) findings, and histological evaluations. Seven participants were enrolled. Maturing repair tissue was observed at the 12-week arthroscopic evaluation. The VAS and IKDC scores were improved at 24 weeks. The improved clinical outcomes were stable over 7 years of follow-up. The histological findings at 1 year showed hyaline-like cartilage. MRI at 3 years showed persistence of the regenerated cartilage. Only five mild to moderate treatment-emergent adverse events were observed. There were no cases of osteogenesis or tumorigenesis over 7 years. The application of this novel stem cell-based medicinal product appears to be safe and effective for the regeneration of durable articular cartilage in osteoarthritic knees.
Tập 6 Số 2 - Trang 613-621 - 2017
Bone Marrow-Derived Mesenchymal Stem Cells-Derived Exosomes Promote Survival of Retinal Ganglion Cells Through miRNA-Dependent Mechanisms Abstract
The loss of retinal ganglion cells (RGC) and their axons is one of the leading causes of blindness and includes traumatic (optic neuropathy) and degenerative (glaucoma) eye diseases. Although no clinical therapies are in use, mesenchymal stem cells (MSC) have demonstrated significant neuroprotective and axogenic effects on RGC in both of the aforementioned models. Recent evidence has shown that MSC secrete exosomes, membrane enclosed vesicles (30–100 nm) containing proteins, mRNA and miRNA which can be delivered to nearby cells. The present study aimed to isolate exosomes from bone marrow-derived MSC (BMSC) and test them in a rat optic nerve crush (ONC) model. Treatment of primary retinal cultures with BMSC-exosomes demonstrated significant neuroprotective and neuritogenic effects. Twenty-one days after ONC and weekly intravitreal exosome injections; optical coherence tomography, electroretinography, and immunohistochemistry was performed. BMSC-derived exosomes promoted statistically significant survival of RGC and regeneration of their axons while partially preventing RGC axonal loss and RGC dysfunction. Exosomes successfully delivered their cargo into inner retinal layers and the effects were reliant on miRNA, demonstrated by the diminished therapeutic effects of exosomes derived from BMSC after knockdown of Argonaute-2, a key miRNA effector molecule. This study supports the use of BMSC-derived exosomes as a cell-free therapy for traumatic and degenerative ocular disease.
Tập 6 Số 4 - Trang 1273-1285 - 2017
Human Mesenchymal Stem Cell Transfusion Is Safe and Improves Liver Function in Acute-on-Chronic Liver Failure Patients Abstract
Acute-on-chronic liver failure (ACLF) is a severe, life-threatening complication, and new and efficient therapeutic strategies for liver failure are urgently needed. Mesenchymal stem cell (MSC) transfusions have been shown to reverse fulminant hepatic failure in mice and to improve liver function in patients with end-stage liver diseases. We assessed the safety and initial efficacy of umbilical cord-derived MSC (UC-MSC) transfusions for ACLF patients associated with hepatitis B virus (HBV) infection. A total of 43 ACLF patients were enrolled for this open-labeled and controlled study; 24 patients were treated with UC-MSCs, and 19 patients were treated with saline as controls. UC-MSC therapy was given three times at 4-week intervals. The liver function, adverse events, and survival rates were evaluated during the 48-week or 72-week follow-up period. No significant side effects were observed during the trial. The UC-MSC transfusions significantly increased the survival rates in ACLF patients; reduced the model for end-stage liver disease scores; increased serum albumin, cholinesterase, and prothrombin activity; and increased platelet counts. Serum total bilirubin and alanine aminotransferase levels were significantly decreased after the UC-MSC transfusions. UC-MSC transfusions are safe in the clinic and may serve as a novel therapeutic approach for HBV-associated ACLF patients.
Tập 1 Số 10 - Trang 725-731 - 2012
Effects of Medium Supplements on Proliferation, Differentiation Potential, and In Vitro Expansion of Mesenchymal Stem Cells Abstract
Mesenchymal stem cells (MSCs) possess great potential for use in regenerative medicine. However, their clinical application may be limited by the ability to expand their cell numbers in vitro while maintaining their differential potentials and stem cell properties. Thus the aim of this study was to test the effect of a range of medium supplements on MSC self-renewal and differentiation potential. Cells were cultured until confluent and subcultured continuously until reaching senescence. Medium supplementation with fibroblast growth factor (FGF)-2, platelet-derived growth factor (PDGF)-BB, ascorbic acid (AA), and epidermal growth factor (EGF) both increased proliferation rate and markedly increased number of cell doublings before reaching senescence, with a greater than 1,000-fold increase in total cell numbers for AA, FGF-2, and PDGF-BB compared with control cultures. Long-term culture was associated with loss of osteogenic/adipocytic differentiation potential, particularly with FGF-2 supplementation but also with AA, EGF, and PDGF-BB. In addition FGF-2 resulted in reduction in expression of CD146 and alkaline phosphatase, but this was partially reversible on removal of the supplement. Cells expressed surface markers including CD146, CD105, CD44, CD90, and CD71 by flow cytometry throughout, and expression of these putative stem cell markers persisted even after loss of differentiation potentials. Overall, medium supplementation with FGF-2, AA, EGF, and PDGF-BB greatly enhanced the total in vitro expansion capacity of MSC cultures, although differentiation potentials were lost prior to reaching senescence. Loss of differentiation potential was not reflected by changes in stem cell surface marker expression.
Tập 1 Số 11 - Trang 771-782 - 2012
Concise Review: Growth Differentiation Factor 15 in Pathology: A Clinical Role? Abstract
Growth differentiation factor 15 (GDF15) is a divergent member of the transforming growth factor β family discovered in a broad range of cells, as indicated by the diversity of its nomenclature. However, the only tissue that expresses a high amount of GDF15 in the physiologic state is placenta. GDF15 is easily detected in blood, and its concentration varies with age. In fact, increased blood concentration of GDF15 is associated with numerous pathological conditions. However, the biological significance underlying these observations is far from clear. GDF15 could have a positive or negative role depending on the state of cells or their environment. Furthermore, study of its biology is hampered by lack of knowledge of its receptor and thus the signaling pathways that drive its action. GDF15 seems to be an integrative signal in pathologic conditions, giving information on severity of disease. Its effectiveness in classifying patients to modulate treatment remains to be shown. Development of therapeutic interventions with GDF15 or anti-GDF15 agents remains difficult until we uncover the mechanism that drives its activity.
Tập 2 Số 12 - Trang 946-952 - 2013
Intranasal delivery of mesenchymal stem cell-derived extracellular vesicles exerts immunomodulatory and neuroprotective effects in a 3xTg model of Alzheimer's disease Abstract The critical role of neuroinflammation in favoring and accelerating the pathogenic process in Alzheimer's disease (AD) increased the need to target the cerebral innate immune cells as a potential therapeutic strategy to slow down the disease progression. In this scenario, mesenchymal stem cells (MSCs) have risen considerable interest thanks to their immunomodulatory properties, which have been largely ascribed to the release of extracellular vesicles (EVs), namely exosomes and microvesicles. Indeed, the beneficial effects of MSC-EVs in regulating the inflammatory response have been reported in different AD mouse models, upon chronic intravenous or intracerebroventricular administration. In this study, we use the triple-transgenic 3xTg mice showing for the first time that the intranasal route of administration of EVs, derived from cytokine-preconditioned MSCs, was able to induce immunomodulatory and neuroprotective effects in AD. MSC-EVs reached the brain, where they dampened the activation of microglia cells and increased dendritic spine density. MSC-EVs polarized in vitro murine primary microglia toward an anti-inflammatory phenotype suggesting that the neuroprotective effects observed in transgenic mice could result from a positive modulation of the inflammatory status. The possibility to administer MSC-EVs through a noninvasive route and the demonstration of their anti-inflammatory efficacy might accelerate the chance of a translational exploitation of MSC-EVs in AD. Significance statement In the attempt to find a possible cure for Alzheimer's disease (AD), mesenchymal stem cells (MSCs) and their derived extracellular vesicles (EVs) are being investigated for therapeutic purposes thanks to their protective and anti-inflammatory properties. The results from this study show that MSC-EVs operate in dampening inflammation (that favors and accelerates the pathogenic process in AD) and in inducing neuroprotective effects. Furthermore, they sustain the delivery of MSC-EVs through the intranasal route, being safe and low invasive, thus laying the foundation for a translational future exploitation of MSC-EVs toward therapy.
Tập 9 Số 9 - Trang 1068-1084 - 2020
Intranasal Administration of Extracellular Vesicles Derived from Human Teeth Stem Cells Improves Motor Symptoms and Normalizes Tyrosine Hydroxylase Expression in the Substantia Nigra and Striatum of the 6-Hydroxydopamine-Treated Rats Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting millions of people worldwide. At present, there is no effective cure for PD; treatments are symptomatic and do not halt progression of neurodegeneration. Extracellular vesicles (EVs) can cross the blood–brain barrier and represent promising alternative to the classical treatment strategies. In the present study, we examined therapeutic effects of intranasal administration of EVs derived from human exfoliated deciduous teeth stem cells (SHEDs) on unilateral 6-hydroxydopamine (6-OHDA) medial forebrain bundle (MFB) rat model of PD. CatWalk gait tests revealed that EVs effectively suppressed 6-OHDA-induced gait impairments. All tested gait parameters (stand, stride length, step cycle, and duty cycle) were significantly improved in EV-treated animals when compared with 6-OHDA-lesion group rats. Furthermore, EVs slowed down numbers of 6-OHDA-induced contralateral rotations in apomorphine test. Improvements in motor function correlated with normalization of tyrosine hydroxylase expression in the striatum and substantia nigra. In conclusion, we demonstrated, for the first time, the therapeutic efficacy of intranasal administration of EVs derived from SHEDs in a rat model of PD induced by 6-OHDA intra-MFB lesion. Our findings could be potentially exploited for the development of new treatment strategies against PD.
Tập 8 Số 5 - Trang 490-499 - 2019