Cellular taxonomy of Hic1(+) mesenchymal progenitor derivatives in the limb: from embryo to adult

Tissue development and regeneration rely on the cooperation of multiple mesenchymal progenitor (MP) subpopulations. We recently identified Hic1 as a marker of quiescent MPs in multiple adult tissues. Here, we describe the embryonic origin of appendicular Hic1(+) MPs and demonstrate that they arise in the hypaxial somite, and migrate into the developing limb at embryonic day 11.5, well after limb bud initiation. 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 specialised mesenchymal derivatives such as, peri and endoneurial cells, pericytes, bone marrow stromal cells, myotenocytes, tenocytes, fascia-resident fibroblasts, with limited contributions to chondrocytes and osteocytes within the skeletal elements. MPs endure within these compartments, continue to express Hic1 and represent a critical reservoir to support post-natal growth and regeneration. Mesenchymal progenitors (MPs) are fundamental to tissue development and regeneration, however, their embryonic origin is unclear. Single cell-omics coupled with lineage tracing reveal a unique somite-derived MP hierarchy in limb morphogenesis.