Cartilage tissue engineering using differentiated and purified induced pluripotent stem cells (original) (raw)
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Rejuvenated Stem/Progenitor Cells for Cartilage Repair Using the Pluripotent Stem Cell Technology
Bioengineering, 2021
It is widely accepted that chondral defects in articular cartilage of adult joints are never repaired spontaneously, which is considered to be one of the major causes of age-related degenerative joint disorders, such as osteoarthritis. Since mobilization of subchondral bone (marrow) cells and addition of chondrocytes or mesenchymal stromal cells into full-thickness defects show some degrees of repair, the lack of self-repair activity in adult articular cartilage can be attributed to lack of reparative cells in adult joints. In contrast, during a fetal or embryonic stage, joint articular cartilage has a scar-less repair activity, suggesting that embryonic joints may contain cells responsible for such activity, which can be chondrocytes, chondroprogenitors, or other cell types such as skeletal stem cells. In this respect, the tendency of pluripotent stem cells (PSCs) to give rise to cells of embryonic characteristics will provide opportunity, especially for humans, to obtain cells car...
Current Molecular Biology Reports, 2016
Articular chondral lesions are major risk factors for the development of osteoarthritis (OA). Multiple adult cellbased approaches have been attempted to restore hyaline cartilage and prevent progressive degeneration; however, the formation of permanent cartilage has not yet been achieved. A scalable source of cartilage progenitors may have far-reaching potential to advance joint cartilage therapy as well as disease modeling and would be expected to facilitate the discovery of novel therapeutics to stimulate cartilage regeneration or prevent degeneration. Because of their unlimited proliferative capacity and pluripotency, human pluripotent stem cells have become an attractive therapeutic option as a source for consistently uniform cells with high chondrogenic capacity. This review focuses on the recent progress using developmentbased paradigms to control the differentiation of human pluripotent stem cells to an articular chondrocyte fate. We highlight recent findings that demonstrate the promise for using pluripotent stem cell-based replacement for hyaline cartilage repair.
Genetically engineered stem cell-based strategies for articular cartilage regeneration
Biotechnology and Applied Biochemistry, 2012
Cartilage is frequently injured, often as a result of inflammatory rheumatic diseases or sports-related trauma. Given its nonvascular nature, articular cartilage has a limited capability for self-repair and currently the few therapeutic options still have uncertain long-term outcomes. Cell-based surgical therapies using autologous chondrocytes to repair cartilage injury have been used in the clinic for over a decade, but this approach has shown mixed results mainly due to the low number of harvested chondrocytes and the loss of cartilage-related phenotype and functionality after several passages of in vitro culture. A wide range of cell sources have been tested to circumvent chondrocyte limitations in cartilage repair, and stem cells have been presented as those that offer the greatest potential for clinical application. This review will focus on recent advances in stem cell-based strategies for articular cartilage repair, specifically focusing on the use of genetically engineered adult stem cells by conventional gene delivery methods and by gene-activated matrices. Perspectives in cartilage engineering are also addressed.
The Potency of Induced Pluripotent Stem Cells in Cartilage Regeneration and Osteoarthritis Treatment
Advances in experimental medicine and biology, 2017
Osteoarthritis (OA) is the most common chronic disabling condition effecting the elderly, significantly impacting an individual patient's quality of life. Current treatment options for OA are focused on pain management and slowing degradation of cartilage. Some modern surgical techniques aimed at encouraging regeneration at defect sites have met with limited long-term success. Mesenchymal stem cells (MSCs) have been viewed recently as a potential tool in OA repair due to their chondrogenic capacity. Several studies have shown success with regards to reducing patient's OA-related pain and discomfort but have been less successful in inducing chondrocyte regeneration. The heterogeneity of MSCs and their limited proliferation capacity also raises issues when developing an off-the-shelf treatment for OA. Induced pluripotent stem cell (iPSC) technology, which allows for the easy production of cells capable of prolonged self-renewal and producing any somatic cell type, may overcome...
The cartilage of joints is long‐lasting (i.e., permanent) cartilage and is not spontane‐ ously repaired after injury in humans. There has been considerable interest in the clinical application of stem cells to the repair of damaged cartilage; however, current cell therapies using adult chondrocytes and mesenchymal stromal cells face problems associated with the low yield of such cells. The expansion culture, needed before transplantation, leads to the formation of fibrocartilage or growth plate-like (i.e., bone‐ forming) cartilage in vivo. Both types of cartilage are unsuitable for the repair of joint cartilage such as meniscus and articular cartilage. Joints are formed during embryo‐ genesis. Therefore, we hypothesize that embryonic progenitor cells responsible for the development of joint cartilage would be the best for regenerating joint cartilage in the adult. Pluripotent stem cells (PSCs) are expected to differentiate in culture into any somatic cell types through processes that mimic embryogenesis, making human (h)PSCs a promising source of embryonic cells for regenerative medicine. However, regardless of the cell system used, the major research goals leading to clinical application to cartilage regeneration are to (1) expand chondrogenic cells (chondro‐ progenitors) to sufficient numbers without loss of their chondrogenic activity, and (2) direct the differentiation of such cells in vivo or in vitro toward articular or other types of chondrocytes of interest. The overall aim of the current review was to provide the basis of a strategy for meeting the goals for cartilage regeneration by the use of hPSC‐ derived chondroprogenitor cells. We provide an overview on signaling mechanisms that are known to affect the expandability and chondrogenic activity of adult and embryonic chondroprogenitors, as well as their differentiation in vivo or in vitro toward a particular type of chondrocyte. We then discuss alternative types of progenitor cells that might replace or combine with the hPSC‐derived chondropro‐ genitors to regenerate permanent cartilage. We also include our recent achievement of successfully expanding hPSC‐derived neural crest to generate ectomesenchymal chondroprogenitors that can be maintained for a long term in culture without loss of chondrogenic activity. Finally, we provide information on the challenges that hPSC progeny‐based regenerative medicine will face, and discuss the implications for such challenges for the future use of PSC progeny to regenerate cartilage.
Isolation, Characterization, and Differentiation of Stem Cells for Cartilage Regeneration
Annals of Biomedical Engineering, 2012
The goal of tissue engineering is to create a functional replacement for tissues damaged by injury or disease. In many cases, impaired tissues cannot provide viable cells, leading to the investigation of stem cells as a possible alternative. Cartilage, in particular, may benefit from the use of stem cells since the tissue has low cellularity and cannot effectively repair itself. To address this need, researchers are investigating the chondrogenic capabilities of several multipotent stem cell sources, including adult and extra-embryonic mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs). Comparative studies indicate that each cell type has advantages and disadvantages, and while direct comparisons are difficult to make, published data suggest some sources may be more promising for cartilage regeneration than others. In this review, we identify current approaches for isolating and chondrogenically differentiating MSCs from bone marrow, fat, synovium, muscle, and peripheral blood, as well as cells from extra-embyronic tissues, ESCs, and iPSCs. Additionally, we assess chondrogenic induction with growth factors, identifying standard cocktails used for each stem cell type. Cellonly (pellet) and scaffold-based studies are also included, as is a discussion of in vivo results.
Rheumatology: Current Research, 2012
Osteoarthritis is a debilitating joint disease present in epidemic proportions worldwide. Osteoarthritis results from degeneration of the articular cartilage of the joint surfaces due to acute trauma, or chronic wear and tear. Due to limited ability of cartilage to repair itself, and lack of available treatments, there is an urgent need for development of approaches to repair articular cartilage damage due to injury or osteoarthritic disease. Cell-based repair strategies are among the most promising of these approaches. Various adult cell sources for cartilage repair are proposed including autologous adult chondrocytes as well as adult Mesenchymal Stem Cells (MSC). Disadvantages such as destructive harvest protocols; poor proliferation, and particularly for MSC, considerable cellular heterogeneity, have limited success of these cell types for cartilage repair. Chondrogenic cells derived from human embryonic stem cells (hESC) offer a highly proliferative cell source, which when directed into the chondrogenic lineage, could provide an ideal source of cells for cartilage repair. Chondrogenic cells derived from human induced pluripotent stem cells (iPSC) offer additional advantages for patient-specific therapy. Recently protocols have been established for directed differentiation of hESC into the chondrogenic lineage. Harnessing the potential of hESC-derived chondrogenic cells will require comprehensive testing of their efficacy for in vivo cartilage repair, as well as considerations of safety and immunogenicity of the cells. Use of pro-chondrogenic factors and/or bioactive scaffolds may assist in optimizing cartilage repair by chondrogenic cells. Repair of cartilage damage in osteoarthritis is a special challenge because of the widespread damage and presence of signals and stressors which disrupt normal joint homeostasis. Particular promise in cell-based repair of osteoarthritis may be provided by chondrogenic progenitor cells which may mimic endogenous repair responses. This review discusses the current status of cell-based cartilage repair strategies and in particular the potential role of hESC-derived chondrocytes or chondroprogenitor cells for treatment of articular cartilage damage due to injury and osteoarthritis.
Stem Cells International, 2018
Due to the restricted intrinsic capacity of resident chondrocytes to regenerate the lost cartilage postinjury, stem cell-based therapies have been proposed as a novel therapeutic approach for cartilage repair. Moreover, stem cell-based therapies using mesenchymal stem cells (MSCs) or induced pluripotent stem cells (iPSCs) have been used successfully in preclinical and clinical settings. Despite these promising reports, the exact mechanisms underlying stem cell-mediated cartilage repair remain uncertain. Stem cells can contribute to cartilage repair via chondrogenic differentiation, via immunomodulation, or by the production of paracrine factors and extracellular vesicles. But before novel cell-based therapies for cartilage repair can be introduced into the clinic, rigorous testing in preclinical animal models is required. Preclinical models used in regenerative cartilage studies include murine, lapine, caprine, ovine, porcine, canine, and equine models, each associated with its specific advantages and limitations. This review presents a summary of recent in vitro data and from in vivo preclinical studies justifying the use of MSCs and iPSCs in cartilage tissue engineering. Moreover, the advantages and disadvantages of utilizing small and large animals will be discussed, while also describing suitable outcome measures for evaluating cartilage repair.
Potential of Human Embryonic Stem Cells in Cartilage Tissue Engineering and Regenerative Medicine
Stem Cell Reviews and Reports, 2010
The current surgical intervention of using autologous chondrocyte implantation (ACI) for cartilage repair is associated with several problems such as donor site morbidity, de-differentiation upon expansion and fibrocartilage repair following transplantation. This has led to exploration of the use of stem cells as a model for chondrogenic differentiation as well as a potential source of chondrogenic cells for cartilage tissue engineering and repair. Embryonic stem cells (ESCs) are advantageous, due to their unlimited self-renewal and pluripotency, thus representing an immortal cell source that could potentially provide an unlimited supply of chondrogenic cells for both cell and tissue-based therapies and replacements. This review aims to present an overview of emerging trends of using ESCs in cartilage tissue engineering and regenerative medicine. In particular, we will be focusing on ESCs as a promising cell source for cartilage regeneration, the various strategies and approaches employed in chondrogenic differentiation and tissue engineering, the associated outcomes from animal studies, and the challenges that need to be overcome before clinical application is possible.