Human Pluripotent Stem Cells: Advances in Chondrogenic Differentiation and Articular Cartilage Regeneration

Current Molecular Biology Reports, Jul 2016

Articular chondral lesions are major risk factors for the development of osteoarthritis (OA). Multiple adult cell-based 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 development-based 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.

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Human Pluripotent Stem Cells: Advances in Chondrogenic Differentiation and Articular Cartilage Regeneration

Human Pluripotent Stem Cells: Advances in Chondrogenic Differentiation and Articular Cartilage Regeneration Rosa M. Guzzo 0 Michael B. O'Sullivan 0 0 Department of Orthopaedic Surgery, UConn Health Center , 263 Farmington Avenue, Farmington, CT , USA 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. Articular cartilage repair; Embryonic stem cells; Induced pluripotent stem cells; Mesenchymal stem cells; Osteoarthritis; Regeneration Introduction Osteoarthritis (OA) is a common and debilitating joint disease for which primary risk factors are traumatic joint injury or mechanical disruption of joint tissues. There is currently no cure for OA. Although the true prevalence of articular chondral lesions in the general public is unknown, approximately 60 % of patients undergoing knee arthroscopy have evidence of cartilage lesions [ 1, 2 ]. The natural history of articular cartilage lesions is poorly understood, as the means for evaluating these lesions (MRI, arthroscopy) are not commonly used for surveillance due to cost implications. A prevailing notion is that chondral lesions increase in size and predispose patients to developing OA. Supporting this idea is evidence that articular cartilage has limited regenerative capacity, is poorly vascularized, and has a small cell-to-matrix volume and a very low mitotic rate [3]. Treatment options for OA patients such as total joint arthroplasty provide excellent outcomes by ameliorating pain and improving function. However, many patients sustain cartilage injuries when they are young and are not good candidates for these procedures as they would outlive their implant and would require multiple revision surgeries [ 2, 4–6 ]. Currently, the prevalence of patients living in the USA with a total hip or total knee arthroplasty is estimated to be 7.2 million, which is higher than the prevalence of stroke (6.8 million) and heart failure (5.1 million) and approaches that of myocardial infarction (7.6 million) [7]. Thus, OA is an important public health issue, and there remains an urgent and growing need to develop regenerative techniques for articular cartilage to treat symptomatic patients and potentially circumvent the onset of OA among individuals predisposed to developing OA. Multiple strategies have been attempted for joint cartilage surface restoration, with the goal of improving joint function and delaying or preventing degeneration. However, regeneration of hyaline cartilage has not been achieved. Introduced by Brittberg et al. in 1994, implantation of in vitro expanded autologous human articular chondrocytes (hACs) is a widely used surgical procedure to treat focal chondral lesions in the knee joint [ 8 ]. Autologous chondrocyte implantation (ACI) involves extraction of a small cartilage biopsy from a nonload-bearing site within the affected knee joint and in vitro expansion of the isolated chondrocytes using Bgood manufacturing practice^ (GMP) laboratory procedures, which is then followed by implantation of these cells to the defect site in a second surgical procedure [ 8 ]. The repair tissue is often fibrocartilaginous, with little hyaline cartilage restoration [ 9, 10 ]. Fibrocartilage generally deteriorates over time because of its inferior structural and mechanical properties, which increases the likelihood of OA and the need for further surgical intervention. Adult mesenchymal stem cells, commonly isolated from bone marrow, have been extensively examined as an alternative to either autologous or allogeneic chondrocytes for regeneration of articular cartilage. These cells offer advantages of ease of harvest using minimally invasive procedures, low immunogenicity, high proliferative indices, and an intrinsic chondrogenic capacity that can be exploited to yield vast quantities of chondroprogenitors to repair cartilage defects [ 11 ]. However, chondrogenic differentiation in bone marrow-derived MSCs (BMSCs) follows an endochondra (...truncated)


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Rosa M. Guzzo, Michael B. O’Sullivan. Human Pluripotent Stem Cells: Advances in Chondrogenic Differentiation and Articular Cartilage Regeneration, Current Molecular Biology Reports, 2016, pp. 113-122, Volume 2, Issue 3, DOI: 10.1007/s40610-016-0041-7