A single cell transcriptional atlas of early synovial joint development

Bian, Qin; Cheng, Yu; Wilson, Jordan; Su, Emily Y.; Kim, Dong Won; Wang, Hong; Yoo, Sooyeon; Blackshaw, Seth; Cahan, Patrick

doi:10.1242/dev.185777

Cited by 33 publications

(37 citation statements)

References 167 publications

(114 reference statements)

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“…The Ucma high and Krt16 high clusters also had a distinct EMC profile with increased expression of several key ECM proteins including Col2a1, Col9a1-a3, and Acan (Figures S4F and S5A). Although the Mef2c high cluster shared several markers with Ucma high and Krt16 high clusters, it showed significant enrichment for markers of pre-hypertrophic/hypertrophic chondrocytes including Ihh, Alpl, Mef2c, Pth1r, and Col10a1 [38,39] suggesting that this cluster may represent pre-hypertrophic/hypertrophic chondrocytes (Figure 2C and S4A,B). We could not obtain significant information about the Neat1 high cluster, as this cluster had minimal genes enriched in its cells.…”

Section: Discussionmentioning

confidence: 99%

“…This human Tnfaip6 high cluster shared markers (Tnfaip6, Abi3bp, Prg4, S100a4, etc.) with the mouse Tnfaip6 high and S100a4 high clusters (Figure 5A,D, Tables S4 and S5) but did not show enrichment for prehypertrophic chondrocyte markers including Ihh, Mef2c, and Pth1r [38][39][40] (Figure 5A,D, Tables S4 and S5). Chil1 (CHI3L1), which marked RegCs [6], was enriched in cluster 2 (Figure 5A,D, Tables S4 and S5).…”

Section: Comparative Transcriptomic Analysis Identified Similarities and Differences Between Mouse And Human Chondrocyte Subtypesmentioning

confidence: 99%

“…These genes were also enriched in clusters 2, 3, and 6, but these clusters had additional clusterspecific markers (Figure S4A,B). Cluster 2 showed enrichment for Mef2c, Ihh, and Pth1r, markers of pre-hypertrophic chondrocytes [38][39][40], and this cluster was named 'Mef2c high ' (Figure 3C,D and S4A). A subset of cell from the Mef2c high cluster also expressed Col10a1, a marker of chondrocyte hypertrophy [38] (Figure S4C).…”

Section: Scrna-seq Analysis Identified Nine Chondrocyte Subtypes In Mouse Knee Jointsmentioning

confidence: 99%

“…We also found that the Mef2c high cluster showed enrichment for many genes associated with 'biomineralization' including Alpl, Sp7, Bglap, and Pth1r, in addition to Mef2c (Figure 4A and S5B). Some of these genes are also associated with pre-hypertrophic/hypertrophic chondrocyte phenotypes and may also reside in the growth plate [38][39][40]43].…”

Section: Molecular and Functional-level Characterization Of Chondrocyte Subpopulationsmentioning

confidence: 99%

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Single-Cell RNA-Seq Reveals Transcriptomic Heterogeneity and Post-Traumatic Osteoarthritis-Associated Early Molecular Changes in Mouse Articular Chondrocytes

Sebastian

McCool

Hum

et al. 2021

Cells

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Articular cartilage is a connective tissue lining the surfaces of synovial joints. When the cartilage severely wears down, it leads to osteoarthritis (OA), a debilitating disease that affects millions of people globally. The articular cartilage is composed of a dense extracellular matrix (ECM) with a sparse distribution of chondrocytes with varying morphology and potentially different functions. Elucidating the molecular and functional profiles of various chondrocyte subtypes and understanding the interplay between these chondrocyte subtypes and other cell types in the joint will greatly expand our understanding of joint biology and OA pathology. Although recent advances in high-throughput OMICS technologies have enabled molecular-level characterization of tissues and organs at an unprecedented resolution, thorough molecular profiling of articular chondrocytes has not yet been undertaken, which may be in part due to the technical difficulties in isolating chondrocytes from dense cartilage ECM. In this study, we profiled articular cartilage from healthy and injured mouse knee joints at a single-cell resolution and identified nine chondrocyte subtypes with distinct molecular profiles and injury-induced early molecular changes in these chondrocytes. We also compared mouse chondrocyte subpopulations to human chondrocytes and evaluated the extent of molecular similarity between mice and humans. This work expands our view of chondrocyte heterogeneity and rapid molecular changes in chondrocyte populations in response to joint trauma and highlights potential mechanisms that trigger cartilage degeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Comparative Transcriptomic Analysis Identified Similarities and Differences Between Mouse And Human Chondrocyte Subtypesmentioning

confidence: 99%

Section: Scrna-seq Analysis Identified Nine Chondrocyte Subtypes In Mouse Knee Jointsmentioning

confidence: 99%

Section: Molecular and Functional-level Characterization Of Chondrocyte Subpopulationsmentioning

confidence: 99%

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Single-Cell RNA-Seq Reveals Transcriptomic Heterogeneity and Post-Traumatic Osteoarthritis-Associated Early Molecular Changes in Mouse Articular Chondrocytes

Sebastian

McCool

Hum

et al. 2021

Cells

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“…New therapeutic approaches, such as cell replacement, and better models would benefit from an improved understanding of synovial joint development at different developmental stages 3 4 . For example, we recently determined the transcriptional programs that regulate early (E12.5 to E15.5) synovial joint development by a combination of single cell RNA-sequencing (scRNA-Seq) of Gdf5-lineage joint progenitors, computational analyses, and in situ validation 5 . While that study uncovered substantial transcriptional and fate bias heterogeneity in interzone cells, it did not characterize how joint progenitors ultimately commit to the major joint cell types, including permanent articular chondrocytes, ligamentocytes, and cells of the menisci and synovium.…”

Section: Introductionmentioning

confidence: 99%

Signaling and transcriptional networks governing late synovial joint development

Bian

Cheng

et al. 2021

Preprint

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Background: During synovial joint development, cavitation marks the end of the emergence of new cell types and the onset of the consolidation of cell type specific programs. However, the transcriptional programs that regulate this crucial stage prior to joint maturation are incompletely characterized. Gdf5-lineage cells give rise to the majority of joint constituents such as articular cartilage, meniscus, ligament, and tendon. Therefore, to explore pre-maturation of the synovial joint, we performed single cell RNA-Seq analysis of 1,306 Gdf5-lineage cells from the murine knee joint at E17.5. Results: Using computational analytics and in situ hybridization, we identified nine sub-states contributing to articular cartilage, meniscus, cruciate ligament, synovium, lining, and surrounding fibrous tissue. We identified a common progenitor population that is predicted to give rise to ligamentaocytes, articular chondrocytes, and lining cells. We further found that while a large number of signaling pathways orchestrate the differentiation of this progenitor to either ligamentocytes or to lining cells, only continued FGF signaling guides these cells to a default chondrocyte fate. Conclusions: Our single cell transcriptional atlas is a resource that can be used to better understand and further study synovial joint development and the reactivation of embryonic programs in diseases such as osteoarthritis.

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Synergistic effects of biological stimuli and flexion induce microcavities promote hypertrophy and inhibit chondrogenesis during in vitro culture of human mesenchymal stem cell aggregates

Zhang,

Berilla,

Cho

et al. 2024

Biotechnology Journal

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Interzone/cavitation are key steps in early stage joint formation that have not been successfully developed in vitro. Further, current models of endochondral ossification, an important step in early bone formation, lack key morphology morphological structures such as microcavities found during development in vivo. This is possibly due to the lack of appropriate strategies for incorporating chemical and mechanical stimuli that are thought to be involved in joint development. We designed a bioreactor system and investigated the synergic effect of chemical stimuli (chondrogenesis‐inducing [CIM] and hypertrophy‐inducing medium [HIM]) and mechanical stimuli (flexion) on the growth of human mesenchymal stem cells (hMSCs) based linear aggregates under different conditions over 4 weeks of perfusion culture. Computational studies were used to evaluate tissue stress qualitatively. After harvesting, both Safranin‐O and hematoxylin & eosin (H&E) staining histology demonstrated microcavity structures and void structures in the region of higher stresses for tissue aggregates cultured only in HIM under flexion. In comparison to either HIM treatment or flexion only, increased glycosaminoglycan (GAG) content in the extracellular matrix (ECM) at this region indicates the morphological change resembles the early stage of joint cavitation; while decreased type II collagen (Col II), and increased type X collagen (Col X) and vascular endothelial growth factor (VEGF) with a clear boundary in the staining section indicates it resembles the early stage of ossification. Further, cell alignment analysis indicated that cells were mostly oriented toward the direction of flexion in high‐stress region only in HIM under flexion, resembling cell morphology in both joint cavitation and hypertrophic cartilage in growth plate. Collectively, our results suggest that flexion and HIM inhibit chondrogenesis and promote hypertrophy and development of microcavities that resemble the early stage of joint cavitation and endochondral ossification. We believe the tissue model described in this work can be used to develop in vitro models of joint tissue for applications such as pathophysiology and drug discovery.

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A single cell transcriptional atlas of early synovial joint development

Cited by 33 publications

References 167 publications

Single-Cell RNA-Seq Reveals Transcriptomic Heterogeneity and Post-Traumatic Osteoarthritis-Associated Early Molecular Changes in Mouse Articular Chondrocytes

Single-Cell RNA-Seq Reveals Transcriptomic Heterogeneity and Post-Traumatic Osteoarthritis-Associated Early Molecular Changes in Mouse Articular Chondrocytes

Signaling and transcriptional networks governing late synovial joint development

Synergistic effects of biological stimuli and flexion induce microcavities promote hypertrophy and inhibit chondrogenesis during in vitro culture of human mesenchymal stem cell aggregates

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