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Elucidation of the fate and function of mesenchymal progenitors in tissue renewal and regeneration

University of British Columbia

Adult tissues contain multiple stem and progenitor cells that are critical for their renewal and regeneration. Tissue resident stem/progenitor populations include mesenchymal progenitors (MPs) whose function and fate are unclear. These studies have been hampered by the lack of suitable solitary markers of these cells which would enable both lineage tracing and functional analyses of MPs. Using a discovery-based approach, the gene Hypermethylated in cancer 1 (Hic1) has been identified as such a marker. Subsequently, two novel knock-in alleles of Hic1 were generated and characterized as part of this project and these analyses showed that Hic1 is restricted to quiescent MPs in muscle and other tissues. Single cell RNA-seq was employed to examine Hic1⁺ cells in muscle and this led to the identification of 3 predominant MP subpopulations with distinct function(s) and lineage potential. Further analysis in muscle injury models revealed that these cells exhibit diverse stage-specific activities, which coordinate multiple aspects of the regenerative process. Following regeneration, Hic1⁺ progeny contribute to several mesenchymal derivatives including Col22a1-expressing cells in the myotendinous junction. In numerous tissues, MPs have been found to play a vital role in stem cell niches. Single cell-seq was employed to characterize MPs across tissues, and these analyses revealed extensive intra and inter-tissue heterogeneity. Within some tissues, unique populations could be identified that appeared based on gene expression to have niche-like properties. This was very evident in the populations characterized from bone marrow (BM), which contribute to the hematopoietic stem cell (HSC) niche. Deletion of Hic1 led to widespread MP hyperplasia, including in the BM. Interestingly, this led to a 2-fold increase in HSC number. Taken together, these results suggest that the Hic1⁺ MPs contribute to the HSC niche and that MP frequency regulates HSC niche capacity. In summary, these findings identify Hic1 as a marker of MPs, and resulting genetic tools have been instrumental in defining MP subpopulations that exhibit transient and enduring roles in regeneration and non-cell autonomous activity in the HSC niche. This provides a solid foundation for understanding MP biology and their utility in cell-based and/or in situ modification to affect health and disease.

Text

2020-05-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/68994

Cell and Developmental Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/