Elbow epicondylar tendinitis is a common problem that usually resolves with nonoperative treatments. When these measures fail, there is a role of Platelet-rich plasma (PRP) for tissue repair.
Elbow epicondylar tendinitis is a common problem that usually resolves with nonoperative treatments. When these measures fail, there is a role of Platelet-rich plasma (PRP) for tissue repair.
Most of studies have focused on subjective and clinical symptoms effect of PRP and fewer papers have studied its objective effect on cartilage. In this study, we investigated the effect of PRP on cartilage characteristics by special MRI sequencings.
Background: Knee osteoarthritis (KOA) is a very challenging condition to treat and can be resistant to medications, procedures, and even surgery. Surgery may not be an option for some patients due to obesity or comorbidities. Regenerative medicine utilizing stem cells, platelet rich plasma (PRP), amniotic fluid, and cytokine modulation is very promising in the treatment of KOA.
Stem cell therapies have been proposed as a treatment option for neurodegenerative diseases, but the best stem cell source and therapeutic efficacy for neuroregeneration remain uncertain. Embryonic stem cells (ESCs) and neural stem cells (NSCs), which can efficiently generate neural cells, could be good candidates but they pose ethical and practical issues. Not only difficult to find the good source of those cells but also they alway pose immunorejection problem since they may not be an autologous cells.
Life expectancy in the developed world has advanced beyond the number of years in which healthy tissue homeostasis can be maintained, and as a result, the number of persons with severe and debilitating chronic illnesses, including cancer, diabetes, osteoarthritis, osteoporosis, neurodegenerative and cardiovascular disease has continued to rise. One of the key underlying causes for the loss in the ability to replenish damaged tissues is the qualitative and quantitative decline in somatic stem cell populations.
Purpose of Review
Osteonecrosis of the femoral head (ONFH) is a common and frequently occurring disease. It is caused by interruption of blood supply with different etiologies. ONFH leads to degeneration and necrosis of the subchondral bone of the femoral head and eventually collapse of the femoral head. ONFH has a high disability rate, seriously affecting the quality of living of patients, and often involves middle-aged and younger people.
Osteoarthritis (OA) is an age related joint disease associated with degeneration and loss of articular cartilage. Consequently, OA patients suffer from chronic joint pain and disability. Weight bearing joints and joints that undergo repetitive stress and excessive ‘wear and tear’ are particularly prone to developing OA. Cartilage has a poor regenerative capacity and current pharmacological agents only provide symptomatic pain relief.
Ligament, cartilage, and meniscus injuries often have poor healing due to low vascularity and low proliferative abilities of the resident cells. Drawbacks with conventional treatment methodologies have prompted interest in a new approach we term "Regenerative Engineering" to regenerate orthopaedic tissues. The work of cells is of central importance in the Regenerative Engineering paradigm. In this regard, both differentiated cells and stem cells such as bone marrow stromal cells have been studied as sources for orthopaedic tissue regeneration. In addition, other stem cells such as those derived from peripheral blood, synovium, adipose, and other extraembryonic sources have been isolated and characterized and subsequently investigated for regenerating various orthopaedic tissues. In this review, recent developments in the stem cell-mediated regeneration of ligament, cartilage, and menisci are discussed.
Mesenchymal stem cells hold the promise to treat not only several congenital and acquired bone degenerative diseases but also to repair and regenerate morbid bone tissues. Utilizing MSCs, several lines of evidences advocate promising clinical outcomes in skeletal diseases and skeletal tissue repair/regeneration. In this context, both, autologous and allogeneic cell transfer options have been utilized. Studies suggest that MSCs are transplanted either alone by mixing with autogenous plasma/serum or by loading onto repair/induction supportive resorb-able scaffolds. Thus, this review is aimed at highlighting a wide range of pertinent clinical therapeutic options of MSCs in the treatment of skeletal diseases and skeletal tissue regeneration. Additionally, in skeletal disease and regenerative sections, only the early and more recent preclinical evidences are discussed followed by all the pertinent clinical studies. Moreover, germane post transplant therapeutic mechanisms afforded by MSCs have also been conversed. Nonetheless, assertive use of MSCs in the clinic for skeletal disorders and repair is far from a mature therapeutic option, therefore, posed challenges and future directions are also discussed. Importantly, for uniformity at all instances, term MSCs is used throughout the review.
Articular cartilage (AC) has limited potential for self-regeneration and damage to AC eventually leads to the development and progression of osteoarthritis (OA). Cell implantation strategies have emerged as a new treatment modality to regenerate AC. Adipose stem cells/adipose-derived stromal cells (ASCs) have gained attention due to their abundance, excellent proliferative potential, and minimal morbidity during harvest. These advantages lower the cost of cell therapy by circumventing time-consuming procedure of culture expansion. ASCs have drawn attention as a potential source for cartilage regeneration since the feasibility of chondrogenesis from ASCs was first reported. After several groups reported inferior chondrogenesis from ASCs, numerous methods were devised to overcome the intrinsic properties. Most in vivo animal studies have reported good results using predifferentiated or undifferentiated, autologous or allogeneic ASCs to regenerate cartilage in osteochondral defects or surgically-induced OA. In this review, we summarize literature on the isolation and in vitro differentiation processes of ASCs, in vivo studies to regenerate AC in osteochondral defects and OA using ASCs, and clinical applications of ASCs.
Objective: Lubricin expression in the superficial cartilage will be a crucial factor in the success of carti-lage regeneration. Mesenchymal stem cells (MSCs) are an attractive cell source and theuse of aggregates of MSCs has some advantages in terms of chondrogenic potential andefficiency of cell adhesion. Lubricin expression in transplanted MSCs has not been fully elu-cidated so far. Our goals were to determine (1) whether cartilage pellets of human MSCs expressed lubricinin vitro chondrogenesis, (2) whether aggregates of human MSCs pro-moted lubricin expression, and (3) whether aggregates of MSCs expressed lubricin in the superficial cartilage after transplantation into osteochondral defects in rats.
Methods: For in vitro analysis, human bone marrow (BM) MSCs were differentiated into cartilage by pellet culture, and also aggregated using the hanging drop technique. For an animal study, aggregates of BM MSCs derived from GFP transgenic rats were transplanted to the osteo- chondral defect in the trochlear groove of wild type rat knee joints. Lubricin expression was mainly evaluated in differentiated and regenerated cartilages.
Results: In in vitro analysis, lubricin was detected in the superficial zone of the pellets and condi-tioned medium. mRNA expression of Proteoglycan4 (Prg4), which encodes lubricin, in pel-lets was significantly higher than that of undifferentiated MSCs. Aggregates showed different morphological features between the superficial and deep zone, and the Prg4 mRNA expression increased after aggregate formation. Lubricin was also found in the aggregate. In a rat study, articular cartilage regeneration was significantly better in the MSC group than in the control group as shown by macroscopical and histological analysis.
Transplantation of mesenchymal stem cells (MSCs) or autologous chondrocytes has been shown to repair damages to articular cartilage due to osteoarthritis (OA). However survival of transplanted cells is considerably reduced in the osteoarthritic environment and it affects successful outcome of the transplantation of the cells. Differentiated chrondroytes derived from adipose stem cells have been proposed as an alternative source and our study investigated this possibility in rats. We investigated the regenerative potential of ASCs and DCs in osteoarthritic environment in the repair of cartilage in rats. We found that ASCs maintained fibroblast morphology in vitro and also expressed CD90 and CD29. Furthermore, ASCs differentiated into chondrocytes, accompanied by increased level of proteoglycans and expression of chondrocytes specific genes, such as, Acan and Col2a1. Histological examination of transplanted knee joints showed regeneration of cartilage tissue compared to control OA knee joints. Increase in gene expression for Acan, Col2a1 with concomitant decrease in the expression of Col1a1 suggested formation of hyaline like cartilage. A significant increase in differentiation index was observed in DCs and ASCs transplanted knee joints (P = 0.0110 vs P = 0.0429) when compared to that in OA control knee joints. Furthermore, transplanted DCs showed increased proliferation along with reduction in apoptosis as compared to untreated control.
In conclusion, DCs showed better survival and regeneration potential as compared with ASCs in rat model of OA and thus may serve a better option for regeneration of osteoarthritic cartilage.
Purpose: Bone marrow concentrate (BMC) and platelet-rich plasma (PRP) are used extensively in regenerative medicine. The aim of this study was to determine differences in the cellular composition and cytokine concentrations of BMC and PRP and to compare two commercial BMC systems in the same patient cohort.
Methods: Patients (29) undergoing orthopaedic surgery were enrolled. Bone marrow aspirate (BMA) was processed to generate BMC from two commercial systems (BMC-A and BMC-B). Blood was obtained to make PRP utilizing the same system as BMC-A. Bone marrow-derived samples were cultured to measure colony-forming units, and flow cytometry was performed to assess mesenchymal stem cell (MSC) markers. Cellular concentrations were assessed for all samples. Catabolic cytokines and growth factors important for cartilage repair were measured using multiplex ELISA.
Results: Colony-forming units were increased in both BMCs compared to BMA (p < 0.0001). Surface markers were consistent with MSCs. Platelet counts were not significantly different between BMC-A and PRP, but there were differences in leucocyte concentrations. TGF-β1 and PDGF were not different between BMC-A and PRP. IL-1ra concentrations were greater (p = 0.0018) in BMC-A samples (13,432 pg/mL) than in PRP (588 pg/mL). The IL-1ra/IL-1β ratio in all BMC samples was above the value reported to inhibit IL-1β.
Conclusions: The bioactive factors examined in this study have differing clinical effects on musculoskeletal tissue. Differences in the cellular and cytokine composition between PRP and BMC and between BMC systems should be taken into consideration by the clinician when choosing a biologic for therapeutic application.
Background: The characteristics and therapeutic potential of subtypes of mesenchymal stem cells (MSCs) are largely unknown. In this study, CD146+ and CD146- MSCs were separated from human umbilical cords, and their effects on regulatory T cells (Tregs), Th17 cells, chondrogenesis, and osteogenesis were investigated.
Methods: Flow cytometry was used to quantify IL-6 and TGF-β1 expressed on CD146+ and CD146- MSCs. The therapeutic potential of both subpopulations was determined by measuring the clinical score and joint histology after intra-articular (IA) transfer of the cells into mice with collagen-induced arthritis (CIA).
Results: Compared with CD146- MSCs, CD146+ MSCs expressed less IL-6 and had a significantly greater effect on chondrogenesis. After T lymphocyte activation, Th17 cells were activated when exposed to CD146- cells but not when exposed to CD146+ cells both in vitro and in vivo. IA injection of CD146+ MSCs attenuated the progression of CIA. Immunohistochemistry showed that only HLA-A+ CD146+ cells were detected in the cartilage of CIA mice. These cells may help preserve proteoglycan expression.
Conclusions: This study suggests that CD146+ cells have greater potency than CD146- cells for cartilage protection and can suppress Th17 cell activation. These data suggest a potential therapeutic application for CD146+ cells in treating inflammatory arthritis.
We propose a method of preparing a novel cell carrier derived from natural cartilage extracellular matrix (ECM), designated cartilage ECM -derived particles (CEDPs). Through a series of processes involving pulverization, sieving, and decellularization, fresh cartilage was made into CEDPs with a median diameter of 263 ±48 μm. Under microgravity culture conditions in a rotary cell culture system (RCCS), bone marrow stromal cells (BMSCs) can proliferate rapidly on the surface of CEDPs with high viability. Histological evaluation and gene expression analysis indicated that BMSCs were differentiated into mature chondrocytes after 21 days of culture without the use of exogenous growth factors. Functional cartilage microtissue aggregates of BMSC-laden CEDPs formed as time in culture increased. Further, the microtissue aggregates were directly implanted into trochlear cartilage defects in a rat model (CEDP+MSC group). Gait analysis and histological results indicated that the CEDP+MSC group obtained better and more rapid joint function recovery and superior cartilage repair compared to the control groups, in which defects were treated with CEDPs alone or only fibrin glue, at both 6 and 12 weeks after surgery. In conclusion, the innovative cell carrier derived from cartilage ECM could promote chondrogenic differentiation of BMSCs, and the direct use of functional cartilage microtissue facilitated cartilage regeneration. This strategy for cell culture, stem cell differentiation and one-step surgery using cartilage microtissue for cartilage repair provides novel prospects for cartilage tissue engineering and may have further broad clinical applications.
The extracellular matrix-associated bone morphogenetic proteins (BMPs) govern a plethora of biological processes. The BMPs are members of the transforming growth factor-β protein superfamily, and they actively participate to kidney development, digit and limb formation, angiogenesis, tissue fibrosis and tumor development. Since their discovery, they have attracted attention for their fascinating perspectives in the regenerative medicine and tissue engineering fields. BMPs have been employed in many preclinical and clinical studies exploring their chondrogenic or osteoinductive potential in several animal model defects and in human diseases. During years of research in particular two BMPs, BMP2 and BMP7 have gained the podium for their use in the treatment of various cartilage and bone defects. In particular they have been recently approved for employment in non-union fractures as adjunct therapies. On the other hand, thanks to their otentialities in biomedical applications, there is a growing interest in studying the biology of mesenchymal stem cell (MSC), the rules underneath their differentiation abilities, and to test their true abilities in tissue engineering. In fact, the specific differentiation of MSCs into targeted celltype lineages for transplantation is a primary goal of the regenerative medicine. This review provides an overview on the current knowledge of BMP roles and signaling in MSC biology and differentiation capacities. In particular the article focuses on the potential clinical use of BMPs and MSCs concomitantly, in cartilage and bone tissue repair.
Introduction: Articular cartilage is renowned for its poor intrinsic capacity for repair. Current treatments for osteoarthritis are limited in their ability to reliably restore the native articular cartilage structure and function. Mesenchymal stem cells (MSCs) present an attractive treatment option for articular cartilage repair, with a recent expansion of clinical trials investigating their use in patients.
Areas covered: This paper provides a current overview of the clinical evidence on the use of MSCs in articular cartilage repair.
Expert opinion: The article demonstrates robust clinical evidence that MSCs have significant potential for the regeneration of hyaline articular cartilage in patients. The majority of clinical trials to date have yielded significantly positive results with minimal adverse effects. However the clinical research is still in its infancy. The optimum MSC source, cell concentrations, implantation technique, scaffold, growth factors and rehabilitation protocol for clinical use are yet to be identified. A larger number of randomised control trials are required to objectively compare the clinical efficacy and long-term safety of the various techniques. As the clinical research continues to evolve and address these challenges, it is likely that MSCs may become integrated into routine clinical practice in the near future.
To advance molecular and cellular therapy into the clinic for peripheral nerve injury, modification of neural scaffolds with the extracellular matrix (ECM) of peripheral nerves has been established as a promising alternative to direct inclusion of support cells and/or growth factors within a neural scaffold, while cell-derived ECM proves to be superior to tissue-derived ECM in the modification of neural scaffolds. Based on the fact that bone marrow mesenchymal stem cells (BMSCs), just like Schwann cells, are adopted as support cells within a neural scaffold, in this study we used BMSCs as parent cells to generate ECM for application in peripheral nerve tissue engineering. A chitosan nerve guidance conduit (NGC) and silk fibroin filamentous fillers were respectively prepared for co-culture with purified BMSCs, followed by decellularization to stimulate ECM deposition. The ECM-modified NGC and lumen fillers were then assembled into a chitosan-silk fibroin-based, BMSC-derived, ECM-modified neural scaffold, which was implanted into rats to bridge a 10 mm-long sciatic nerve gap. Histological and functional assessments after implantation showed that regenerative outcomes achieved by our engineered neural scaffold were better than those achieved by a plain chitosan-silk fibroin scaffold, and suggested the benefits of BMSC-derived ECM for peripheral nerve repair. Copyright
Adipose-derived stem cells (ADSCs) have myocardial regeneration potential, and transplantation of these cells following myocardial infarction (MI) in animal models leads to modest improvements in cardiac function. We hypothesized that pharmacological priming of pre-transplanted ADSCs would further improve left ventricular functional recovery after MI. We previously identified a compound from a family of 3,5-disubstituted isoxazoles, ISX1, capable of activating an Nkx2-5-driven promoter construct. Here, using ADSCs, we found that ISX1 (20 mM, 4 days) triggered a robust, dose-dependent, fourfold increase in Nkx2-5 expression, an early marker of cardiac myocyte differentiation and increased ADSC viability in vitro. Co-culturing neonatal cardiomyocytes with ISX1-treated ADSCs increased early and late cardiac gene expression. Whereas ISX1 promoted ADSC differentiation toward a cardiogenic lineage, it did not elicit their complete differentiation or their differentiation into mature adipocytes, osteoblasts, or chondrocytes, suggesting that re-programming is cardiomyocyte specific. Cardiac transplantation of ADSCs improved left ventricular functional recovery following MI, a response which was significantly augmented by transplantation of ISX1- pretreated cells. Moreover, ISX1-treated and transplanted ADSCs engrafted and were detectable in the myocardium 3 weeks following MI, albeit at relatively small numbers. ISX1 treatment increased histone acetyltransferase (HAT) activity in ADSCs, which was associated with histone 3 and histone 4 acetylation. Finally, hearts transplanted with ISX1-treated ADSCs manifested significant increases in neovascularization, which may account for the improved cardiac function. These findings suggest that a strategy of drug-facilitated initiation of myocyte differentiation enhances exogenously transplanted ADSC persistence in vivo, and consequent tissue neovascularization, to improve cardiac function.
In recent years, it has become clear that mechanical cues play an integral role in maintaining stem cell functions. Here we discuss how integrating physical approaches and engineering principles in stem cell biology, including culture systems, preclinical models, and functional assessment, may improve clinical application in regenerative medicine.