Runx2+ Niche Cells Maintain Incisor Mesenchymal Tissue Homeostasis through IGF Signaling

Abstract

SUMMARY Stem cell niches provide a microenvironment to support the self-renewal and multi-lineage differentiation of stem cells. Cell-cell interactions within the niche are essential for maintaining tissue homeostasis. However, the niche cells supporting mesenchymal stem cells (MSCs) are largely unknown. Using single-cell RNA sequencing, we show heterogeneity among Gli1+ MSCs and identify a subpopulation of Runx2+/Gli1+ cells in the adult mouse incisor. These Runx2+/Gli1+ cells are strategically located between MSCs and transit-amplifying cells (TACs). They are not stem cells but help to maintain the MSC niche via IGF signaling to regulate TAC proliferation, differentiation, and incisor growth rate. ATAC-seq and chromatin immunoprecipitation reveal that Runx2 directly binds to Igfbp3 in niche cells. This Runx2-mediated IGF signaling is crucial for regulating the MSC niche and maintaining tissue homeostasis to support continuous growth of the adult mouse incisor, providing a model for analysis of the molecular regulation of the MSC niche.

The vital role of Gli1+ mesenchymal stem cells in tissue development and homeostasis

“…A subpopulation of Runx2 + /Gli1 + cells, strategically located between MSCs and TA cells, was found not to be stem cells but responsible for maintaining the MSCs niche and TA cells' function (Chen, Jing, et al, 2020).…”

Arid1a regulates cell cycle exit of transit-amplifying cells by inhibiting the Aurka-Cdk1 axis in mouse incisor

“…This reduction may be caused by the overactivated proliferation of TACs after loss of Arid1a through negative feedback, which is distinct from previous studies on the positive feedback mechanism between TACs and MSCs. For example, loss of TAC proliferation caused by deletion of Ring1b (also known as Rnf2) leads to reduction of MSCs via a positive feedback mechanism (An et al, 2018); reduced TAC proliferation after loss of Runx2 in the Gli1+ lineage also decreases the MSC population via positive feedback (Chen et al, 2020). The potential negative feedback between increased TACs and reduced MSCs found in our study highlights the complex nature of TAC-MSC crosstalk, which may involve both positive and negative feedback mechanisms.…”

“…For example, PRC1, which is a well-known epigenetic regulator, is highly expressed in mesenchymal TACs in mouse incisor; it maintains TAC proliferation by controlling Wnt/β-catenin signaling and inhibiting Cdkn2a while activating cyclin E2 and other positive cell-cycle regulators (An et al, 2018). Our recent study has shown that IGF signaling is important for Runx2+ niche cells, which reside between MSCs and TACs in the mouse incisor, to promote the proliferation of TACs (Chen et al, 2020). In addition, Notch signaling and Dlk1 are indispensable for maintaining TACs in the mouse incisor (Walker et al, 2019).…”

Single-Cell Atlas Reveals Fatty Acid Metabolites Regulate the Functional Heterogeneity of Mesenchymal Stem Cells

“…Recent advanced single-cell studies have further explored the heterogeneity of bone marrow MSCs with distinct differentiation potential (Baryawno et al, 2019;Leimkuhler et al, 2020). Furthermore, researchers also identified an IL-10 regulated metabolically active mature adipocyte subtype from subcutaneous adipose tissue (Rajbhandari et al, 2019) and Runx2 + /Gli1 + cells in the adult mouse incisor, which maintains Gli1 + MSCs (Chen et al, 2020).…”