A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1 ⁺ smooth muscle progenitor cells

Abstract

We characterize a sonic hedgehog (Shh) signaling domain restricted to the adventitial layer of artery wall that supports resident Sca1-positive vascular progenitor cells (AdvSca1). Using patched-1 (Ptc1 lacZ ) and patched-2 (Ptc2 lacZ ) reporter mice, adventitial Shh signaling activity was first detected at embryonic day (E) 15.5, reached the highest levels between postnatal day 1 (P1) and P10, was diminished in adult vessels, and colocalized with a circumferential ring of Shh protein deposited between the media and adventitia. In Shh ؊/؊ mice, AdvSca1 cells normally found at the aortic root were either absent or greatly diminished in number. Using a Wnt1-cre lineage marker that identifies cells of neural crest origin, we found that neither the adventitia nor AdvSca1 cells were labeled in arteries composed of neural crest-derived smooth muscle cells (SMCs). Although AdvSca1 cells do not express SMC marker proteins in vivo, they do express transcription factors thought to be required for SMC differentiation, including serum response factor (SRF) and myocardin family members, and readily differentiate to SMC-like cells in vitro. However, AdvSca1 cells also express potent repressors of SRF-dependent transcription, including Klf4, Msx1, and FoxO4, which may be critical for maintenance of the SMC progenitor phenotype of AdvSca1 cells in vivo. We conclude that a restricted domain of Shh signaling is localized to the arterial adventitia and may play important roles in maintenance of resident vascular SMC progenitor cells in the artery wall.artery ͉ differentiation ͉ Klf4 ͉ self-renewal ͉ serum response factor

Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis

“…2H). In agreement with these results, adventitial cells have been shown to respond to Hh signals (28). Because oncogenic Smo expression within pancreatic epithelium was unable to potentiate Kras G12D -mediated neoplasia, we tested whether Hh signaling was active in Kras G12D -driven tumor epithelium by crossing PdxCre;Kras G12D ;SmoM2 mice with the Ptc-LacZ reporter line.…”

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

“…The outer layer or tunica adventitia is populated by adventitial fibroblasts, is rich in collagen, does not contain elastic fibers, and is separated by the tunica media by the external elastic lamina (reviewed in Wagenseil and Mecham 2009). Some studies have suggested that the adventitial layer contains progenitors that trans-differentiate into VSMCs (Sartore et al 2001;Hoofnagle et al 2004;Hu et al 2004;Passman et al 2008). The composition of the ECM secreted by vascular cell types, and by VSMCs in particular, varies depending on the type of blood vessel and in response to developmental, physiological, and pathological stimuli (Kelleher et al 2004;Xu and Shi 2014).…”

Vascular Stem Cells in Vascular Remodeling and Diseases

“…(6) The Sca1 expression mentioned earlier in the adventitia has been independently confirmed in mouse aorta and mesenteric and femoral arteries. (25) More importantly, Sca1 + cells immune-selected from the aortic adventitia were found capable of smooth muscle and endothelial differentiation. Moreover, when the Sca1-selected cells were treated with Bone Morphogenetic Protein 2 (BMP2), colonies formed that stained positive by alizarin red, suggesting osteogenic differentiation.…”

“…(18,19) Multiple studies have demonstrated that vascular mesenchymal cells, including microvascular pericytes, so-called calcifying vascular cells and SMCs, undergo osteochondrogenic lineage differentiation spontaneously or under special conditions such as hyperphosphatemia. (18,20) In recent times, these traditional views of vascular biology have been revised by the discovery of immature stem/progenitor cell populations, relevant to endothelial (21,22), smooth muscle (23)(24)(25), myeloid (26) and multipotent mesenchymal lineage (27) that have been shown to participate in postnatal vasculogenesis and vascular wall remodeling. An increasing body of evidence points to the existence of these different progenitor cell types within embryonic, fetal and adult vessel walls, where they may reside either constitutively or appear as a result of circulating migration.…”

“…(24,90,97,98) In addition, an intriguing possibility is that adventitial Sca1+ progenitor cells may be stimulated by arterial injury to adopt an SMC-like phenotype and migrate into the media and possibly into the intima, and thereby participate in neointimal formation. (24,25) Development of new cell therapeutics based on detailed understanding of generation of VSCs holds great promise.…”