Lung Stem Cell Differentiation in Mice Directed by Endothelial Cells via a BMP4-NFATc1-Thrombospondin-1 Axis

Abstract

SUMMARY Lung stem cells are instructed to produce lineage-specific progeny through unknown factors in their microenvironment. We used clonal three-dimensional (3D) co-cultures of endothelial cells and distal lung stem cells, bronchioalveolar stem cells (BASCs), to probe the instructive mechanisms. Single BASCs had bronchiolar and alveolar differentiation potential in lung endothelial cell co-cultures. Gain and loss of function experiments showed BMP4-Bmpr1a signaling triggers calcineurin/NFATc1-dependent expression of Thrombospondin-1 (Tsp1) in lung endothelial cells to drive alveolar lineage-specific BASC differentiation. Tsp1-null mice exhibited defective alveolar injury repair, confirming a crucial role for the BMP4-NFATc1-TSP1 axis in lung epithelial differentiation and regeneration in vivo. Discovery of this pathway points to methods to direct the derivation of specific lung epithelial lineages from multipotent cells. These findings elucidate a pathway that may be a critical target in lung diseases and provide new tools to understand the mechanisms of respiratory diseases at the single cell level.

Human endothelial colony-forming cells serve as trophic mediators for mesenchymal stem cell engraftment via paracrine signaling

“…For example, signals from bone marrow microvascular ECs are essential for selfrenewal and repopulation of hematopoietic stem cells (12). Similarly, EC-derived paracrine signals stimulate self-renewal and in situ expansion of stem cells residing in lung, liver, and neural tissues, contributing to the regeneration of these tissues upon injury (13,14). Despite this trophic potential, current therapeutic uses of ECFCs remain largely focused on harnessing their inherent blood vessel-forming capacity.…”

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

“…Bronchioalveolar stem cell lineage-specific differentiation was found to be supported by TSP1 (132). Furthermore, renal tubule epithelial cells harvested from kidneys of young male Cd47 -/-mice had constitutive upregulation of stem cell transcription factors compared with cells from kidneys from WT mice (217).…”

“…In contrast, endogenous H 2 S produced by CSE induces differentiation and maturation of primary osteoblasts, resulting in induction of osteopontin and BMP2 expression (315). This is mediated by sulfhydration of the transcription factor RUNX2 at Cys 123 and Cys 132 and results in elevated BMP2, osteopontin, and osteocalcin expression (Fig. 8A).…”

The Progress of BMP4 on the Role of Ocular Development and Eye Diseases

“…Thus, the expression of BMP2, BMP4 and its receptor in adult corneal cells was demonstrated. Keratinocyte proliferation and apoptosis can be regulated (Lee et al, 2014). It was found that the expression of BMP4 in keratoconus was higher by identifying differentially expressed genes between keratoconus and normal corneal cells (Allison et al, 2016).…”

“…BMP4 can inhibit the growth (Kallioniemi, 2012) of tumor cells and promote lung development (Lee et al, 2014). BMP4 can mediate apoptosis of retinal vascular endothelial cells and inhibit angiogenesis (Lynch et al, 2016).…”