<i>GDF5+</i> chondroprogenitors derived from human pluripotent stem cells preferentially form permanent chondrocytes

Pothiawala, Azim; Sahbazoglu, Berke E; Ang, Bryan; Matthias, Nadine; Pei, Guangsheng; Yan, Qing; Davis, Brian R.; Huard, Johnny; Zhao, Zhongming; Nakayama, Naoki

doi:10.1242/dev.196220

Cited by 3 publications

(2 citation statements)

References 77 publications

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“…Hypertrophic2 IZ transitions through Hypertrophic1 in the inferred trajectory and the former expressed genes that are upregulated during formation of anlagen or pre-hypertrophic chondrocytes in mice (BMP5, HAPLN1, ACAN and ZFHX3) 19,25 , suggesting they form the incipient cartilage template. Overall, our in vivo data are consistent with in vitro observations of the propensity for human-iPSC and mouse-ESC derived GDF5 + stromal cells to form an articular, rather than a hypertrophic phenotype 26,27 .…”

Section: Spatiotemporal Zonation Of the Incipient Synovial Jointssupporting

confidence: 88%

A multiomic atlas of human early skeletal development

To,

Fei,

Pett

et al. 2024

Preprint

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Bone and joint formation in the developing skeleton rely on co-ordinated differentiation of progenitors in the nascent developing limbs and joints. The cell states, epigenetic processes and key regulatory factors underlying their lineage commitment to osteogenic and other mesenchymal populations during ossification and joint formation remain poorly understood and are largely unexplored in human studies. Here, we apply paired single-nuclei transcriptional and epigenetic profiling of 336,000 droplets, in addition to spatial transcriptomics, to construct a comprehensive atlas of human bone, cartilage and joint development in the shoulder, hip, knee and cranium from 5 to 11 post-conception weeks. Spatial mapping of cell clusters to our highly multiplexed in situ sequencing (ISS) data using our newly developed tool ISS-Patcher revealed new cellular mechanisms of zonation during bone and joint formation. Combined modelling of chromatin accessibility and RNA expression allowed the identification of the transcriptional and epigenetic regulatory landscapes that drive differentiation of mesenchymal lineages including osteogenic and chondrogenic lineages, and novel chondrocyte cell states. In particular, we define regionally distinct limb and cranial osteoprogenitor populations and trajectories across the fetal skeleton and characterise differential regulatory networks that govern intramembranous and endochondral ossification. Through somatic mutation analysis, we predict two new potential cell origins for human chondrocyte development. We also introduce SNP2Cell, a tool to link cell-type specific regulatory networks to numerous polygenic traits such as osteoarthritis. We also conduct in silico perturbations of genes that cause monogenic craniosynostosis and implicate potential pathogenic cell states and disease mechanisms involved. This work forms a detailed and dynamic regulatory atlas of human fetal skeletal maturation and advances our fundamental understanding of cell fate determination in human skeletal development.

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Section: Spatiotemporal Zonation Of the Incipient Synovial Jointssupporting

confidence: 88%

A multiomic atlas of human early skeletal development

To,

Fei,

Pett

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…These findings align with a recent study by Pothiawala et al, which identified a subpopulation of iPSC derivatives capable of generating and maintaining a "true" permanent-like articular cartilage phenotype that does not progress towards endochondral ossification. 39 They identified a chondroprogenitor population positive for GDF5 derived from iPSC-derived mesenchymal cells along the paraxial mesodermal lineage. Collectively, our study highlights the potential of iPSC derivatives in generating hyaline-like cartilage for the repair of joint defects.…”

Section: Discussionmentioning

confidence: 99%

Autologous iPSC- and MSC-derived Chondrocyte Implants for Cartilage Repair in a Miniature Pig Model

Lee,

Sivapatham,

Leiferman

et al. 2023

Preprint

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Induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (iMSCs) have greater potential for generating chondrocytes without hypertrophic and fibrotic phenotypes compared to bone marrow-derived mesenchymal stem/stromal cells (BMSCs). However, there is a lack of research demonstrating the use of autologous iMSCs for repairing articular chondral lesions in large animal models. In this study, we aimed to evaluate the effectiveness of autologous miniature pig (minipig) iMSC-chondrocyte (iMSC-Ch)-laden implants in comparison to autologous BMSC-chondrocyte (BMSC-Ch)-laden implants for cartilage repair in porcine femoral condyles. iMSCs and BMSCs were seeded into fibrin glue/nanofiber constructs and cultured with chondrogenic induction media for 7 days before implantation. To assess the regenerative capacity of the cells, 19 skeletally mature Yucatan minipigs were randomly divided into microfracture control, acellular scaffold, iMSC, and BMSC subgroups. A cylindrical defect measuring 7 mm in diameter and 0.6 mm in depth was created on the articular cartilage surface without violating the subchondral bone. The defects were then left untreated or treated with acellular or cellular implants. Both cellular implant-treated groups exhibited enhanced joint repair compared to the microfracture and acellular control groups. Immunofluorescence analysis yielded significant findings, showing that cartilage treated with iMSC-Ch implants exhibited higher expression of COL2A1 and minimal to no expression of COL1A1 and COL10A1, in contrast to the BMSC-Ch-treated group. This indicates that the iMSC-Ch implants generated more hyaline cartilage-like tissue compared to the BMSC-Ch implants. These results contribute to filling the knowledge gap regarding the potential of autologous iPSC derivatives for cartilage repair in translational animal models.

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