Odd skipped-related 1 (Osr1) identifies a population of embryonic fibro-adipogenic progenitors regulating myogenesis during limb development
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE78056 | GEO | 2017/07/28
SECONDARY ACCESSION(S): PRJNA312476
REPOSITORIES: GEO
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Project description:We isolated Osr1-expressing cells (Osr1 GCE/+) via FACS-sorting from E13.5 axillary, inguinal and cervical regions of a mouse embryo and analysed the gene expression profile of 10,000 cells through single-cell RNA-seq.
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Project description:Purpose: To study the requirement of Osr1 expression for FAP function during skeletal muscle regeneration. Methods: We sequenced total mRNAs isolated from adult FAPs FACS sorted from 3 and 7 day post injured hindlimb skeletal muscle of Ctrl (Osr1flox/+ CAGG Cre+) and Osr1 cKO (Osr1flox/flox CAGG Cre+) mice. Results: Loss of Osr1 leads to pro-fibrotic orientation of FAPs and impairs both FAP-macrophage and FAP-MuSCs communication network resulting in impaired regenerative myogenesis and persistent fibrosis. Conclusions: Osr1 is a key transcriptional regulator of FAP regenerative function protecting FAPs from assuming a detrimental pro-fibrotic and anti-myogenic state.
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Project description:Fibro-adipogenic progenitors (FAPs) are an interstitial cell population in adult skeletal muscle that support muscle regeneration. During development, interstitial muscle connective tissue (MCT) cells support proper muscle patterning, however the underlying molecular mechanisms are not well understood and it remains unclear whether adult FAPs and embryonic MCT cells share a common lineage. We show here that mouse embryonic limb MCT cells expressing the transcription factor Osr1, differentiate into fibrogenic and adipogenic cells in vivo and in vitro defining an embryonic FAP-like population. Genetic lineage tracing shows that developmental Osr1+ cells give rise to a subset of adult FAPs. Loss of Osr1 function leads to a reduction of myogenic progenitor proliferation and survival resulting in limb muscle patterning defects. Transcriptome and functional analyses reveal that Osr1+ cells provide a critical pro-myogenic niche via the production of MCT specific extracellular matrix components and secreted signaling factors.
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2019-06-20 | E-MTAB-8040 | biostudies-arrayexpress
Project description:Fatty infiltration, the ectopic deposition of adipose tissue within skeletal muscle, is mediated via the adipogenic differentiation of fibro-adipogenic progenitors (FAPs). We used single-nuclei and single-cell RNA sequencing to characterize FAP heterogeneity in patients with fatty infiltration. We identified an MME+ FAP subpopulation which, based on ex vivo characterization as well as transplantation experiments, exhibits high adipogenic potential. MME+ FAPs are characterized by low activity of WNT, known to control adipogenic commitment, and are refractory to the inhibitory role of WNT activators. Using preclinical models for muscle damage versus fatty infiltration, we show that many MME+ FAPs undergo apoptosis during muscle regeneration and differentiate into adipocytes under pathological conditions, leading to a reduction in their abundance. Finally, we utilized the varying fat infiltration levels in human hip muscles and found less MME+ FAPs in fatty infiltrated human muscle. Altogether, we have identified the dominant adipogenic FAP subpopulation in skeletal muscle.
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Project description:The tongue is a muscular organ in the vertebrate oral cavity that performs complex functions in daily life, including feeding and phonetic articulation. The tongue consists of mesenchyme cells of two distinct origins: the muscle cells are derived from occipital somites whereas the tendons and other connective tissues derived from the cranial neural crest. Cranial neural crest cells are important for the initiation of tongue swelling and proper patterning of intrinsic and extrinsic tongue muscle groups. However, little is known regarding the molecular and cellular mechanisms of tongue morphogenesis. We show that the odd-skipped related 1 (Osr1) transcription factor exhibits dynamic expression in the tongue mesenchyme during early tongue development. Tissue-specific inactivation of Osr1 in the early neural crest cells resulted in ectopic cartilage formation in the mouse tongue. We show that Sox9, the master regulator of chondrocyte differentiation, is initially widely expressed in the neural crest derived mesenchyme in the tongue and subsequently down-regulated concomitant by up-regulation of Osr1 expression. Osr1 mutant embryos exhibit persistent expression of Sox9 and chondrocyte differentiation from the neural crest derived tongue mesenchyme. Further biochemical analyses indicate that Osr1 may directly suppresses Sox9 gene expression in the tongue mesenchyme. These data reveal a novel mechanism in suppression of chondrogenic fate during tongue development. Remarkably, the ectopic cartilage in the Osr1 mutant mice resembles the entoglossal cartilage naturally develops in the avian tongue. These results suggest that modulation of expression of Osr1 may underline the evolutionary divergence in tongue cartilage formation. RNAs were isolated from microdissected E12 embryonic mouse tongue of Osr1f/-;Wnt1cre and control littermates and characterized by RNAseq
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