PDGFRβ Signaling Regulates Mural Cell Plasticity and Inhibits Fat Development

Abstract

SUMMARY Mural cells (pericytes and vascular smooth muscle cells) provide trophic and structural support to blood vessels. Vascular smooth muscle cells alternate between a synthetic/proliferative state and a differentiated/contractile state, but the dynamic states of pericytes are poorly understood. To explore the cues that regulate mural cell differentiation and homeostasis, we have generated conditional knock-in mice with activating mutations at the PDGFRβ locus. We show that increased PDGFRβ signaling drives cell proliferation and downregulates differentiation genes in aortic vascular smooth muscle. Increased PDGFRβ signaling also induces a battery of immune response genes in pericytes and mesenchymal cells, and inhibits differentiation of white adipocytes. Mural cells are emerging as multipotent progenitors of pathophysiological importance, and we identify PDGFRβ signaling as an important in vivo regulator of their progenitor potential.

Human Perivascular Stem Cell-Based Bone Graft Substitute Induces Rat Spinal Fusion

“…Currently, there now exists ample experimental proof that perivascular cells give rise in culture to mesenchymal stem cells [72], but the relevance of these observations to a possible natural role of perivascular cells as progenitors/regenerative cells in vivo is far less clear. The use of reporter mice has, however, recently brought evidence that perivascular cells-in particular pericytes-can act in situ as progenitors of white adipocytes [73], satellite cells and muscle fibers [74], follicular dendritic cells [75], and multiple other mesodermal cells [76]. Pericytes are also involved in myofibroblast generation and fibrosis development in the kidney, heart, and skeletal muscle [77].…”

Heterogeneity of adipose tissue in development and metabolic function

“…Further, conditional knock-in mice with activating mutations in the PdgfRβ locus showed that increased PdgfRβ signaling in pericytes affects WAT development during the early days of postnatal life (P3-P13). Despite initial differentiation of some adipocytes, WAT failed to fully develop in PdgfRβ overexpressing mice, with SAT showing reduced lipids but a higher cell density and only a rudimentary mWAT depot (Olson and Soriano, 2011). Therefore, it has been assumed that pericytes represent WAT progenitors, and proper PdgfRβ signaling is required to guarantee progenitor potential (Olson and Soriano, 2011;Tang et al, 2008).…”

“…Transgenic mice expressing GFP under the control of the α-SMA (α-smooth muscle actin) promoter, a common marker for pericytes, showed that α-SMA + , but not α-SMA − cells, are multipotent in vitro, and represent a stem cell population in adipose tissue (Cai et al, 2011;Cawthorn et al, 2012). PdgfRβ ( platelet-derived growth factor receptor β), NG2 (neural/glial antigen 2) and α-SMA are known markers for mural cells (Olson and Soriano, 2011;Tang et al, 2008) that were used to show that mural cells express Pparγ ( peroxisome proliferator-activated receptor γ) (Tang et al, 2008). A PdgfRβ reporter mouse strain confirmed that adipocyte progenitors indeed derive from mural cells and that these cells are exclusively present in adipose tissue depots (Tang et al, 2008).…”

Notch3 establishes brain vascular integrity by regulating pericyte number

“…Pdgfb/Pdgfrβ signaling can promote pericyte proliferation (Olson and Soriano, 2011) and in cell culture constitutively active Notch3 can elevate Pdgfrb expression (Jin et al, 2008), raising the possibility that Notch3 regulates pericyte number and vascular integrity, at least in part, by regulating Pdgfrb transcription. We performed two experiments to investigate whether Notch3 and Pdgfrβ function in a common pathway to regulate pericyte development in vivo.…”