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UBC Theses and Dissertations

Origin, fate, and function of embryonic Hic1-positive mesenchymal progenitors in the developing limb Arostegui, Martin


Tissue development and regeneration rely on the cooperation of multiple mesenchymal progenitor (MP) subpopulations. Recently, the gene Hypermethylated in cancer 1 ( Hic1) has been identified as a marker of quiescent MPs in multiple adult tissues. Hic1⁺ MPs have since been implicated in the repair and regeneration of several organs such as skeletal muscle (SkM), skin, heart, and brain. While the roles that Hic1⁺ MPs play in tissue maintenance are currently being elucidated, knowledge surrounding their developmental origin and fate is lacking. Using the developing forelimb as a model system, we describe the embryonic origin of Hic1⁺ MPs and demonstrate that they first appear in the developing limb ~48 hours after limb bud initiation at embryonic day (E) 11.5 and represent a rare subset of the total mesenchymal cell population. Time-resolved single cell-omics analyses coupled with lineage tracing reveal that Hic1⁺ cells generate a unique MP hierarchy, that includes both recently identified adult universal fibroblast populations (Dpt⁺, Pi16⁺ and Dpt⁺, Col15a1⁺) and more specialized mesenchymal derivatives such as, peri- and endo-neural cells, pericytes, bone marrow stromal cells (BMSCs), myotenocytes, tenocytes, and fascia-resident fibroblasts, with limited contributions to chondrocytes and osteocytes within the skeletal elements. We further demonstrate that, in the adult organism, MPs endure within these compartments, continue to express Hic1 and represent a critical reservoir to support post-natal growth and regeneration. Within the appendicular skeleton, Hic1⁺ descendants do not contribute to the primary skeletal anlagen but represent the elusive MP population that generate progeny which connect bone to tendon (entheses) and tendon to muscle (myotendinous junction). Furthermore, deletion of Hic1 leads to skeletal defects reflective of deficient muscle-bone coupling. Collectively, these findings demonstrate that Hic1 identifies a unique MP population that contributes to multiple cell lineages during limb development. Furthermore, Hic1⁺ MPs are crucial for appendicular skeletogenesis as their progeny primarily constitute several forelimb tendon-bone and tendon-muscle attachment regions. As parallels between tissue regeneration and embryonic development are being increasingly made, understanding the origin and fate of heterogenous tissue-resident MPs will support efforts aimed at promoting regeneration in mature tissues.

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