Steric Interference of Adhesion Supports In-Vitro Chondrogenesis of Mesenchymal Stem Cells on Hydrogels for Cartilage Repair.
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ABSTRACT:
SUBMITTER: Goldshmid R
PROVIDER: S-EPMC4585928 | biostudies-other | 2015
REPOSITORIES: biostudies-other
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Project description:BackgroundArticular cartilage diseases are considered a major health problem, and tissue engineering using human mesenchymal stem cells (MSCs) have been shown as a promising solution for cartilage tissue repair. Hesperidin is a flavonoid extract from citrus fruits with anti-inflammatory properties. We aimed to investigate the effect of hesperidin on MSCs for cartilage tissue repair. MSCs were treated by hesperidin, and colony formation and proliferation assays were performed to evaluate self-renewal ability of MSCs. Alcian blue staining and Sox9 expression were measured to evaluate chondrogenesis of MSCs. Secretion of pro-inflammatory cytokines IFN-γ, IL-2, IL-4 and IL-10, and expression of nuclear factor kappa B (NF-κB) subunit p65 were also assessed.ResultsHesperidin improved self-renewal ability and chondrogenesis of MSCs, inhibited secretion of pro-inflammatory cytokines IFN-γ, IL-2, IL-4 and IL-10, and suppressed the expression of p65. Overexpression of p65 was able to reverse the hesperidin inhibited secretions of pro-inflammatory cytokines, and abolish the enhancing effect of hesperidin on chondrogenesis of MSCs.ConclusionHesperidin could serve as a therapeutic agent to effectively enhance chondrogenesis of human MSCs by inhibiting inflammation to facilitate cartilage tissue repair.
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Project description:Cartilage degeneration is associated with degenerative bone and joint processes in severe osteoarthritis (OA). Spontaneous cartilage regeneration is extremely limited. Often the treatment consists of a partial or complete joint implant. Adipose-derived stem cell (ASC) transplantation has been shown to restore degenerated cartilage; however, regenerative differences of ASC would depend on the source of adipose tissue. The infra- and suprapatellar fat pads surrounding the knee offer a potential autologous source of ASC for patients after complete joint substitution. When infrapatellar- and suprapatellar-derived stromal vascular fractions (SVF) were compared, a significantly higher CD105 (+) population was found in the suprapatellar fat. In addition, the suprapatellar SVF exhibited increased numbers of colony formation units and a higher population doubling in culture compared to the infrapatellar fraction. Both the suprapatellar- and infrapatellar-derived ASC were differentiated in vitro into mature adipocytes, osteocytes, and chondrocytes. However, the suprapatellar-derived ASC showed higher osteogenic and chondrogenic efficiency. Suprapatellar-derived ASC transplantation in a severe OA mouse model significantly diminished the OA-associated knee inflammation and cartilage degenerative grade, significantly increasing the production of glycosaminoglycan and inducing endogenous chondrogenesis in comparison with the control group. Overall, suprapatellar-derived ASC offer a potential autologous regenerative treatment for patients with multiple degenerative OA.
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Project description:The production of a clinically useful engineered cartilage is an outstanding and unmet clinical need. High-throughput RNA sequencing provides a means of characterizing the molecular phenotype of populations of cells and can be leveraged to better understand differences among source cells, derivative engineered tissues, and target phenotypes. In this study, small RNA sequencing is utilized to comprehensively characterize the microRNA transcriptomes (miRNomes) of native human neonatal articular cartilage and human bone marrow-derived mesenchymal stem cells (hBM-MSCs) differentiating into cartilage organoids, contrasting the microRNA regulation of engineered cartilage with that of a promising target phenotype. Five dominant microRNAs are upregulated during cartilage organoid differentiation and disproportionately regulate transcription factors: miR-148a-3p, miR-140-3p, miR-27b-3p, miR-140-5p, and miR-181a-5p. Two microRNAs that dominate the miRNomes of hBM-MSCs, miR-21-5p and miR-143-3p, persist throughout the differentiation process and may limit the ability of these cells to differentiate into an engineered cartilage resembling target native articular cartilage. By using predictive bioinformatics tools and antagomir inhibition, these persistent microRNAs are shown to destabilize the mRNA of genes with known or potential roles in cartilage biology including FGF18, TGFBR2, TET1, STOX2, ARAP2, N4BP2L1, LHX9, NFIA, and RPS6KA5. These results shed light on the extent to which only a few microRNAs contribute to the complex regulatory environment of hBM-MSCs for engineered tissues. Impact statement MicroRNAs are emerging as important controlling elements in the differentiation of human bone marrow-derived mesenchymal stem cells (hBM-MSCs). By using a robust bioinformatic approach and further validation in vitro, here we provide a comprehensive characterization of the microRNA transcriptomes (miRNomes) of a commonly studied and clinically promising source of multipotent cells (hBM-MSCs), a gold standard model of in vitro chondrogenesis (hBM-MSC-derived cartilage organoids), and an attractive in vivo target phenotype for clinically useful engineered cartilage (neonatal articular cartilage). These analyses highlighted a specific set of microRNAs involved in the chondrogenic program that could be manipulated to acquire a more robust articular cartilage-like phenotype. This characterization provides researchers in the cartilage tissue engineering field a useful atlas with which to contextualize microRNA involvement in complex differentiation pathways.
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Project description:Tissue engineering strategies for repairing and regenerating articular cartilage face critical challenges to recapitulate the dynamic and complex biochemical microenvironment of native tissues. One approach to mimic the biochemical complexity of articular cartilage is through the use of recombinant bacterial collagens as they provide a well-defined biological 'blank template' that can be modified to incorporate bioactive and biodegradable peptide sequences within a precisely defined three-dimensional system. We customized the backbone of a Streptococcal collagen-like 2 (Scl2) protein with heparin-binding, integrin-binding, and hyaluronic acid-binding peptide sequences previously shown to modulate chondrogenesis and then cross-linked the recombinant Scl2 protein with a combination of matrix metalloproteinase 7 (MMP7)- and aggrecanase (ADAMTS4)-cleavable peptides at varying ratios to form biodegradable hydrogels with degradation characteristics matching the temporal expression pattern of these enzymes in human mesenchymal stem cells (hMSCs) during chondrogenesis. hMSCs encapsulated within the hydrogels cross-linked with both degradable peptides exhibited enhanced chondrogenic characteristics as demonstrated by gene expression and extracellular matrix deposition compared to the hydrogels cross-linked with a single peptide. Additionally, these combined peptide hydrogels displayed increased MMP7 and ADAMTS4 activities and yet increased compression moduli after 6 weeks, suggesting a positive correlation between the degradation of the hydrogels and the accumulation of matrix by hMSCs undergoing chondrogenesis. Our results suggest that including dual degradation motifs designed to respond to enzymatic activity of hMSCs going through chondrogenic differentiation led to improvements in chondrogenesis. Our hydrogel system demonstrates a bimodal enzymatically degradable biological platform that can mimic native cellular processes in a temporal manner. As such, this novel collagen-mimetic protein, cross-linked via multiple enzymatically degradable peptides, provides a highly adaptable and well defined platform to recapitulate a high degree of biological complexity, which could be applicable to numerous tissue engineering and regenerative medicine applications.
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Project description:Osteoarthritis (OA) is a degenerative disease of the connective tissue and progresses with age in the older population or develops in young athletes following sports-related injury. The articular cartilage is especially vulnerable to damage and has poor potential for regeneration because of the absence of vasculature within the tissue. Normal load-bearing capacity and biomechanical properties of thinning cartilage are severely compromised during the course of disease progression. Although surgical and pharmaceutical interventions are currently available for treating OA, restoration of normal cartilage function has been difficult to achieve. Since the tissue is composed primarily of chondrocytes distributed in a specialized extracellular matrix bed, bone marrow stromal cells (BMSCs), also known as bone marrow-derived 'mesenchymal stem cells' or 'mesenchymal stromal cells', with inherent chondrogenic differentiation potential appear to be ideally suited for therapeutic use in cartilage regeneration. BMSCs can be easily isolated and massively expanded in culture in an undifferentiated state for therapeutic use. Owing to their potential to modulate local microenvironment via anti-inflammatory and immunosuppressive functions, BMSCs have an additional advantage for allogeneic application. Moreover, by secreting various bioactive soluble factors, BMSCs can protect the cartilage from further tissue destruction and facilitate regeneration of the remaining progenitor cells in situ. This review broadly describes the advances made during the last several years in BMSCs and their therapeutic potential for repairing cartilage damage in OA.
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Project description:Articular cartilage repair remains a significant and growing clinical challenge with the aging population. The native extracellular matrix (ECM) of articular cartilage is a 3D structure composed of proteinaceous fibers and a hydrogel ground substance that together provide the physical and biological cues to instruct cell behavior. Here we present fibrous scaffolds composed of poly(vinyl alcohol) and the biological cue chondroitin sulfate with fiber dimensions on the nanoscale for application to articular cartilage repair. The unique, low-density nature of the described nanofiber scaffolds allows for immediate cell infiltration for optimal tissue repair. The capacity for the scaffolds to facilitate cartilage-like tissue formation was evaluated in vitro. Compared with pellet cultures, the nanofiber scaffolds enhance chondrogenic differentiation of mesenchymal stems cells as indicated by increased ECM production and cartilage specific gene expression while also permitting cell proliferation. When implanted into rat osteochondral defects, acellular nanofiber scaffolds supported enhanced chondrogenesis marked by proteoglycan production minimally apparent in defects left empty. Furthermore, inclusion of chondroitin sulfate into the fibers enhanced cartilage-specific type II collagen synthesis in vitro and in vivo. By mimicking physical and biological cues of native ECM, the nanofiber scaffolds enhanced cartilaginous tissue formation, suggesting their potential utility for articular cartilage repair.
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Project description:Lacking self-repair abilities, injuries to articular cartilage can lead to cartilage degeneration and ultimately result in osteoarthritis. Tissue engineering based on functional bioactive scaffolds are emerging as promising approaches for articular cartilage regeneration and repair. Although the use of cell-laden scaffolds prior to implantation can regenerate and repair cartilage lesions to some extent, these approaches are still restricted by limited cell sources, excessive costs, risks of disease transmission and complex manufacturing practices. Acellular approaches through the recruitment of endogenous cells offer great promise for in situ articular cartilage regeneration. In this study, we propose an endogenous stem cell recruitment strategy for cartilage repair. Based on an injectable, adhesive and self-healable o-alg-THAM/gel hydrogel system as scaffolds and a biophysio-enhanced bioactive microspheres engineered based on hBMSCs secretion during chondrogenic differentiation as bioactive supplement, the as proposed functional material effectively and specifically recruit endogenous stem cells for cartilage repair, providing new insights into in situ articular cartilage regeneration.
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Project description:Mesenchymal stem cells (MSCs) are a promising cell source for cartilage tissue engineering given their chondrogenic potential. This potential has yet to be fully realized, as the mechanical properties of MSC-based constructs are lower than those of chondrocyte-based constructs cultured identically. The aim of this study was to better understand the transcriptional underpinnings of this functional limitation. Matched chondrocytes and MSCs from three donors were cultured in agarose in a defined medium containing transforming growth factor beta3 (TGF-beta3). We evaluated the compressive mechanical properties and matrix deposition of maturing constructs over 56 days. Transcriptional differences between the two cell types were assessed on day 0 and 28 via microarray analysis and real-time polymerase chain reaction; differential deposition of matrix molecules was assessed by immunohistochemistry. Although the mechanical and biochemical properties of cell-seeded constructs improved with culture duration, MSC values plateaued at day 28, and remained lower than chondrocyte values. Using microarray analysis, 324 genes were identified as mis-expressed during chondrogenesis. Differential expression of 18 genes was validated, and differential deposition of proteoglycan 4 and TGF-beta-induced 68 kDa protein (TGFBI) was confirmed. Temporal expression profiles of these 18 genes showed that some genes were never expressed (chondromodulin), some were expressed at lower levels (proteoglycan 4), and some were expressed only at later time points (TGFBI) in MSCs compared to chondrocytes. These findings further define the complex transcriptional topography of MSC chondrogenesis, and provide new benchmarks for optimizing the growth of MSC-based engineered cartilage.
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Project description:Fibrin and alginate hydrogels have been widely used to support chondrogenesis of bone marrow-derived mesenchymal stem cells (BM-MSCs) for articular cartilage and fibrocartilage tissue engineering, with each material offering distinct advantages and disadvantages. Attempting to produce a gel scaffold exhibiting beneficial characteristics of both materials, we fabricated fibrin/alginate blended hydrogels at various blend ratios and evaluated the gel morphology, mechanical properties and their support for BM-MSC chondrogenesis. Results show that when the fibrin/alginate ratio decreased, the fibrin architecture transitioned from uniform to interconnected fibrous and finally to disconnected islands against an alginate background, with opposing trends in the alginate architecture. Fibrin maintained gel extensibility and promoted cell proliferation, while alginate improved the gel biostability and better supported glycosaminoglycan and collagen II production and chondrogenic gene expression. Blended gels had physical and biological characteristics intermediate between fibrin and alginate. Of the blends examined, FA 40:8 (40 mg ml(-1) fibrinogen blended with 8 mg ml(-1) alginate) was found to be the most appropriate group for future studies on tension-driven BM-MSC fibrochondrogenesis. As BM-MSC differentiation appeared to vary between fibrin and alginate regions of blended scaffolds, this study also highlighted the potential to develop spatially heterogeneous tissues through manipulating the heterogeneity of scaffold composition.
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Project description:Inconsistent therapeutic efficacy of mesenchymal stem cells (MSCs) in regenerative medicine has been documented in many clinical trials. Precise prediction on the therapeutic outcome of a MSC therapy based on the patient's conditions would provide valuable references for clinicians to decide the treatment strategies. In this article, we performed a meta-analysis on MSC therapies for cartilage repair using machine learning. A small database was generated from published in vivo and clinical studies. The unique features of our neural network model in handling missing data and calculating prediction uncertainty enabled precise prediction of post-treatment cartilage repair scores with coefficient of determination of 0.637 ± 0.005. From this model, we identified defect area percentage, defect depth percentage, implantation cell number, body weight, tissue source, and the type of cartilage damage as critical properties that significant impact cartilage repair. A dosage of 17 - 25 million MSCs was found to achieve optimal cartilage repair. Further, critical thresholds at 6% and 64% of cartilage damage in area, and 22% and 56% in depth were predicted to significantly compromise on the efficacy of MSC therapy. This study, for the first time, demonstrated machine learning of patient-specific cartilage repair post MSC therapy. This approach can be applied to identify and investigate more critical properties involved in MSC-induced cartilage repair, and adapted for other clinical indications.
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