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Compensatory growth and recovery of tissue cytoarchitecture after transient cartilage-specific cell death in foetal mouse limbs

ABSTRACT: A major question in developmental and regenerative biology is how organ size is controlled by progenitor cells. For example, while limb bones exhibit catch-up growth (recovery of a normal growth trajectory after transient developmental perturbation), it is unclear how this emerges from the behaviour of chondroprogenitors, the cells sustaining the cartilage anlagen that are progressively replaced by bone. Here we show that transient sparse cell death in the mouse foetal cartilage was repaired postnatally, via a two-step process. During injury, progression of chondroprogenitors towards more differentiated states was delayed, leading to altered cartilage cytoarchitecture and impaired bone growth. Then, once cell death was over, chondroprogenitor differentiation was accelerated and cartilage structure recovered, including partial rescue of bone growth. At the molecular level, ectopic activation of mTORC1 correlated with, and was necessary for, part of the recovery, revealing a specific candidate to be explored during normal growth and in future therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE235779 | GEO | 2024/03/11

REPOSITORIES: GEO

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Project description:Background: Human pluripotent stem cells (hPSCs) give rise to chondrogenic activity in culture. Such activity was found in mesodermal and neural crest like progeny of hPSCs, and readily expanded as SOX9+ msenchymal cells in a medium containing FGF2. However, once expanded, the type of chondrocytes they perfer to form is growth plate-ike transient chondrocytes that are destined to form bone. However, we have recently developed a method to generate GDF5+ mesenchymal cells from such SOX9+ cells which ehibit activity to preferentially form articular-like permanent chondrocytes. The aim of the present prospective follow-up study was to reveal the cell-type and developmental origin of the GDF5+ cells as well as the SOX9+ cells. Methods: Paraxial mesoderm was generated from human PSCs, purified by FACS, and expanded to generate SOX9+ chondroprogenitors. Then, the SOX9+ cells were further differentiated into joint progenitor-like GDF5+ chondroprogenitors. These two chondroprogenitors were subjcted to bulk RNA-seq. Results: Based on the transcriptomic data, we examined differentially expressed genes, cell-type deconvolution analysis, and cell-type correlation analysis. The results suggested that GDF5+ cells might contain a teno/ligamento-genic potential (e.g., SCX+ cells), while SOX9+ cells were related to (neural crest-derived) ectomesenchymal chondroprogenitors. The followup biological analyses indicated as follows. The fast-growing SOX9+ cells formed cartilage that expressed chondrocyte hypertrophy markers and was readily mineralized after ectopic transplantation. In contrast, the slowly-growing GDF5+ cells were derived from SOX9+ cells. They formed cartilage that tended to express low to no chondrocyte hypertrophy markers, while expressing PRG4, a marker of embryonic articular chondrocytes, and to remain largely unmineralized in vivo. Conclusions: Our results imply that GDF5+ cells specified to generate permanent-like cartilage are likely to emerge in association with the commitment of SOX9+ cells to the tendon/ligament lineage.

Project description:Cartilage plays a fundamental role in the development of the human skeleton. Early in embryogenesis, mesenchymal cells condense and differentiate to chondrocytes to shape the early skeleton. Subsequently, the cartilage anlagen differentiate to form the growth plates, which are responsible for linear bone growth, and the articular chondrocytes, which facilitate joint function. However, despite the multiplicity of roles of cartilage during human fetal life, surprisingly little is known about its transcriptome. To address this, a whole genome microarray expression profile was generated using RNA isolated from 18-22 week human distal femur fetal cartilage and compared with a database of control normal human tissues aggregated at UCLA, termed CELSIUS. From the wealth of data, 161 cartilage-selective genes were identified, defined as genes significantly expressed in cartilage with low expression and little variation across a panel of 34 non-cartilage tissues. Among these 161 genes were cartilage-specific genes such as collagen genes and 25 genes which have been associated with skeletal phenotypes in humans and/or mice. Many of the other cartilage-selective genes do not have established roles in cartilage or are novel, unannotated genes. Quantitative RT-PCR confirmed the unique pattern of gene expression observed by microarray analysis. Defining the gene expression pattern for cartilage has identified new genes that may contribute to human skeletogenesis as well as provided further candidate genes for skeletal dysplasias. The data suggest that fetal cartilage is a complex and transcriptionally active tissue and demonstrate that the set of genes selectively expressed in the tissue has been greatly underestimated. Experiment Overall Design: RNA from 7 normal fetal cartilage samples was isolated. 5 samples were run in duplicate on U133 2.0 arrays, while 2 were run on U133A and U133B subsets. In brief, cartilage selective genes were identified by comparing 5 normal cartilage samples (GSM149638,GSM149639 ,GSM149640,GSM149641 ,GSM149642) to normal tissue expression profiles found on CELCIUS at UCLA. Genes which were found expressed at significantly higher levels were validated for their elevated and specific expression using the three platforms. The 9 validation arrays are: 5 U133 2.0 (GSM149643 ,GSM149644 ,GSM149645 ,GSM149646,GSM149647), 2 U133A (GSM149651, GSM149652), 2 U133B (GSM149653, GSM149654)

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Compensatory growth and recovery of tissue cytoarchitecture after transient cartilage-specific cell death in foetal mouse limbs

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