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Limb connective tissue is organized in a continuum of promiscuous fibroblast identities during development

ABSTRACT: Although connective tissues play critical roles in development, our understanding of connective tissue fibroblast developmental programs lag behind that of other components of the musculoskeletal system mainly because fibroblasts are highly heterogeneous and poorly characterized. Combining single-cell RNA-sequencing-based strategies, including trajectory inference, and in situ hybridization analyses, we address the diversity of connective tissue fibroblasts and their developmental trajectories during chicken limb foetal development. We show that fibroblasts switch from a positional information to a lineage diversification program during their development. Muscle connective tissue and tendon contain several fibroblast populations that emerge asynchronously. In fine, these populations map to distinct layers, prefiguring the adult fibroblast layers. Populations that are close in transcriptional identity are found in neighboring layers. Altogether, we propose that the limb connective tissue is organised in a continuum of promiscuous fibroblasts identities, allowing for the robust and efficient connection of highly different tissues such as muscle, bone and skin.

ORGANISM(S): Gallus gallus

PROVIDER: GSE261503 | GEO | 2024/07/19

REPOSITORIES: GEO

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Project description:A fundamental question in biology is how an undifferentiated field of cells acquires spatial pattern and undergoes coordinated differentiation. The development of the vertebrate limb is an important paradigm for understanding these processes. The skeletal and connective tissues of the developing limb all derive from a population of multipotent progenitor cells located in its distal tip. During limb outgrowth, these progenitors segregate into a chondrogenic lineage, located in the center of the limb bud, and soft connective tissue lineages located in its periphery. We report that the interplay of two families of signaling proteins, fibroblast growth factors (FGFs) and Wnts, coordinate the growth of the multipotent progenitor cells with their simultaneous segregation into these lineages. FGF and Wnt signals act together to synergistically promote proliferation while maintaining the cells in an undifferentiated, multipotent state, but act separately to determine cell lineage specification. Withdrawal of both signals results in cell cycle withdrawal and chondrogenic differentiation. Continued exposure to Wnt however, maintains proliferation and re-specifies the cells towards the soft connective tissue lineages. We have identified target genes that are synergistically regulated by Wnts and Fgfs, and show how these factors actively suppress differentiation and promote growth. Finally, we show how the spatial restriction of Wnt and FGF signals to the limb ectoderm and to a specialized region of it, the apical ectodermal ridge, controls the distribution of cell behaviors within the growing limb, and guides the proper spatial organization of the differentiating tissues. Keywords: transcriptional response to growth factor treatment Cells derived from mouse embryonic stage 11.5 limb buds were cultured and treated with purified Wnt3a protein or vehicle controls. The transcriptional response was detected using spotted cDNA microarrays after 2 hrs or 4 hrs of treatment. 4 biological replicates were used per condition.

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Limb connective tissue is organized in a continuum of promiscuous fibroblast identities during development

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