Chondrocytes Derived From Mesenchymal Stromal Cells and Induced Pluripotent Cells of Patients With Familial Osteochondritis Dissecans Exhibit an Endoplasmic Reticulum Stress Response and Defective Matrix Assembly

Xu, Maojia; Stattin, Eva; Shaw, Georgina; Heinegård, Dick; Sullivan, Gareth J.; Wilmut, Ian; Colman, Alan; Önnerfjord, Patrik; Khabut, A.; Aspberg, Anders; Dockery, Peter; Hardingham, Timothy E.; Murphy, Mary; Barry, Frank

doi:10.5966/sctm.2015-0384

Cited by 36 publications

(39 citation statements)

References 41 publications

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“…Although more research is needed in order to optimise the current protocols for differentiating iPSCs into chondrocytes 7 , here we demonstrate that the iPSC-lines derived from patients with OA of the hand show less capacity to produce extracellular matrix rich in COL and PGs, after the differentiation process, in comparison to the iPSC-line derived from the healthy donor. These preliminary results are in accordance with previous studies in which the extracellular matrix of chondrocytes derived from patients' iPSC resembled the one observed during advanced OA 11 .…”

Section: Discussionsupporting

confidence: 92%

“…The potential of iPSCs is irrefutable because they can be used as an abundant, accessible, and autologous cell source with differentiation potential to develop human in vitro models while bypassing ethical concerns. In fact, several studies have been recently developed using patient-specific iPSCs [10][11][12] for modeling cartilage and other aging-related diseases 13 such as rheumatoid arthritis and knee OA 14,15 .…”

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confidence: 99%

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Generation and characterization of human induced pluripotent stem cells (iPSCs) from hand osteoarthritis patient-derived fibroblasts

Castro-Viñuelas

Sanjurjo‐Rodríguez

Piñeiro-Ramil

et al. 2020

Sci Rep

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Knowledge and research results about hand osteoarthritis (hOA) are limited due to the lack of samples and animal models of the disease. Here, we report the generation of two induced pluripotent stem cell (iPSC)-lines from patients with radiographic hOA. Furthermore, we wondered whether these iPSC-lines carried single nucleotide polymorphisms (SNPs) within genes that have been associated with hOA. Finally, we performed chondrogenic differentiation of the iPSCs in order to prove their usefulness as cellular models of the disease. We performed a non-integrative reprogramming of dermal fibroblasts obtained from two patients with radiographic rhizarthrosis and non-erosive hOA by introducing the transcriptional factors Oct4, Sox2, Klf4 and c-Myc using Sendai virus. After reprogramming, embryonic stem cell-like colonies emerged in culture, which fulfilled all the criteria to be considered iPSCs. Both iPSC-lines carried variants associated with hOA in the four studied genes and showed differences in their chondrogenic capacity when compared with a healthy control iPSC-line. To our knowledge this is the first time that the generation of iPSC-lines from patients with rhizarthrosis and non-erosive hOA is reported. The obtained iPSC-lines might enable us to model the disease in vitro, and to deeper study both the molecular and cellular mechanisms underlying hOA. Osteoarthritis (OA) is a prevalent musculoskeletal disease that affects the joints, and it has a substantial effect on quality life 1-4. Hand OA affects predominantly the carpometacarpal joint (CMCJ), followed by the interphalangeal joints (IPJs), both proximal and distal 4. OA of the CMCJ, also known as rhizarthrosis or thumb OA, is the most common location in women over 55 years, and the severity is usually linked to handedness. Mechanical pain at the base of the thumb and the thenar eminence are the principal clinical manifestations of this pathology 5. Erosive hand OA is another form that may involve the CMCJ of the thumb as well as IPJs, in which central erosions are found in the subcondral bone 4. Although both the individual and the societal burden of hand OA are well known, knowledge and research results about its underlying cellular and molecular mechanisms are limited 3 , mainly due to the dearth of tissue samples and lack of animal models of this pathology 4,6. Cellular in vitro models are meaningful tools to shed light on the molecular mechanisms and pathways that are involved in hand OA. Primary chondrocytes, immortalized cell lines and mesenchymal stromal cells are commonly used as in vitro models of OA 6. However, they present

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Generation and characterization of human induced pluripotent stem cells (iPSCs) from hand osteoarthritis patient-derived fibroblasts

Castro-Viñuelas

Sanjurjo‐Rodríguez

Piñeiro-Ramil

et al. 2020

Sci Rep

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“…Regarding cartilage diseases, most of the studies focus on monogenic cartilage-diseases. For example, Xu et al (2016), using an in vitro model of familiar osteochondritis dissecans based on the employment of iPSCs, reveal that several characteristics of the differentiated chondrocytes can help in explaining the disease phenotype and susceptibility to cartilage injury. Studying chondrocytes differentiated from patients' MSCs and iPSCs, large deregulation and aberration in assembled extracellular matrix and deregulated cell fate are found, which are caused by an abnormal accumulation of mutated aggrecan protein.…”

Section: Disease Modellingmentioning

confidence: 99%

“…Studying chondrocytes differentiated from patients' MSCs and iPSCs, large deregulation and aberration in assembled extracellular matrix and deregulated cell fate are found, which are caused by an abnormal accumulation of mutated aggrecan protein. Moreover, the composition of the extracellular matrix in patients' iPSC-derived chondrocytes reflects the changes seen in advanced osteoarthritis (OA), presenting further evidence of the association between familial osteochondritis dissecans and early-onset OA (Xu et al, 2016). Patient-derived skeletal dysplasia iPSCs are generated by Saitta et al (2014) to study early stages of aberrant cartilage formation in vitro.…”

Section: Disease Modellingmentioning

confidence: 99%

Induced pluripotent stem cells for cartilage repair: current status and future perspectives

Castro-Viñuelas¹,

Sanjurjo‐Rodríguez²,

Piñeiro-Ramil³

et al. 2018

eCM

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The establishment of cartilage regenerative medicine is an important clinical issue, but the search for cell sources able to restore cartilage integrity proves to be challenging. Human mesenchymal stromal cells (MSCs) are prone to form epiphyseal or hypertrophic cartilage and have an age-related limited proliferation. On the other hand, it is difficult to obtain functional chondrocytes from human embryonic stem cells (ESCs). Moreover, the ethical issues associated with human ESCs are an additional disadvantage of using such cells. Since their discovery in 2006, induced pluripotent stems cells (iPSCs) have opened many gateways to regenerative medicine research, especially in cartilage tissue engineering therapies. iPSCs have the capacity to overcome limitations associated with current cell sources since large numbers of autologous cells can be derived from small starting populations. Moreover, problems associated with epiphyseal or hypertrophiccartilage formation can be overcome using iPSCs. iPSCs emerge as a promising cell source for treating cartilage defects and have the potential to be used in the clinical field. For this purpose, robust protocols to induce chondrogenesis, both in vitro an in vivo, are required. This review summarises the recent progress in iPSC technology and its applications for cartilage repair.

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“…8). Regardless of the fact that the induction time was greatly shortened with the help of L2C4S4 extracts, the SOX9, and Aggrecan synthesized by the new-derived chondrocytes are comparable to those from other induction methods [23,24].…”

Section: Discussionmentioning

confidence: 70%

A lithium-containing biomaterial promotes chondrogenic differentiation of induced pluripotent stem cells with reducing hypertrophy

Chen

Gao

et al. 2020

Stem Cell Res Ther

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Background: Induced pluripotent stem cells (iPSCs) exhibit limitless pluripotent plasticity and proliferation capability to provide an abundant cell source for tissue regenerative medicine. Thus, inducing iPSCs toward a specific differentiation direction is an important scientific question. Traditionally, iPSCs have been induced to chondrocytes with the help of some small molecules within 21-36 days. To speed up the differentiation of iPSCs, we supposed to utilize bioactive ceramics to assist chondrogenic-induction process. Methods: In this study, we applied ionic products (3.125~12.5 mg/mL) of the lithium-containing bioceramic (Li 2 Ca 4 Si 4 O 13 , L2C4S4) and individual Li + (5.78~23.73 mg/L) in the direct chondrogenic differentiation of human iPSCs. Results: Compared to pure chondrogenic medium and extracts of tricalcium phosphate (TCP), the extracts of L2C4S4 at a certain concentration range (3.125~12.5 mg/mL) significantly enhanced chondrogenic proteins Type II Collagen (COL II)/Aggrecan/ SRY-Box 9 (SOX9) synthesis and reduced hypertrophic protein type X collagen (COL X)/matrix metallopeptidase 13 (MMP13) production in iPSCs-derived chondrocytes within 14 days, suggesting that these newly generated chondrocytes exhibited favorable chondrocytes characteristics and maintained a low-hypertrophy state. Further studies demonstrated that the individual Li + ions at the concentration range of 5.78~23.73 mg/L also accelerated the chondrogenic differentiation of iPSCs, indicating that Li + ions played a pivotal role in chondrogenic differentiation process.Conclusions: These findings indicated that lithium-containing bioceramic with bioactive specific ionic components may be used for a promising platform for inducing iPSCs toward chondrogenic differentiation and cartilage regeneration.

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Chondrocytes Derived From Mesenchymal Stromal Cells and Induced Pluripotent Cells of Patients With Familial Osteochondritis Dissecans Exhibit an Endoplasmic Reticulum Stress Response and Defective Matrix Assembly

Cited by 36 publications

References 41 publications

Generation and characterization of human induced pluripotent stem cells (iPSCs) from hand osteoarthritis patient-derived fibroblasts

Generation and characterization of human induced pluripotent stem cells (iPSCs) from hand osteoarthritis patient-derived fibroblasts

Induced pluripotent stem cells for cartilage repair: current status and future perspectives

A lithium-containing biomaterial promotes chondrogenic differentiation of induced pluripotent stem cells with reducing hypertrophy

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