Calcineurin initiates smooth muscle differentiation in neural crest stem cells

Abstract

The process of vascular smooth muscle cell (vSMC) differentiation is critical to embryonic angiogenesis. However, despite its importance, the vSMC differentiation program remains largely undefined. Murine gene disruption studies have identified several gene products that are necessary for vSMC differentiation, but these methodologies cannot establish whether or not a factor is sufficient to initiate the differentiation program. A gain-of-function system consisting of normal vSMC progenitor cells would serve as a useful complement to whole animal loss-of-function studies. We use such a system here, namely freshly isolated rat neural crest stem cells (NCSCs), to show that activation of the calcineurin signaling pathway is sufficient to drive these cells toward a smooth muscle fate. In addition, we present data suggesting that transforming growth factor (TGF)-β1, which also causes NCSCs to differentiate into smooth muscle, activates calcineurin signaling in NCSCs, leading to a model in which activation of calcineurin signaling is the mechanism by which TGF-β1 causes SMC differentiation in these cells.

Pertussis Toxin (PTX) B Subunit and the Nontoxic PTX Mutant PT9K/129G Inhibit Tat-Induced TGF-β Production by NK Cells and TGF-β-Mediated NK Cell Apoptosis

“…In addition, Tat itself has been reported to induce apoptosis through this mechanism (16,17). In muscle cells, TGF-␤ has also been shown to activate calcineurin, a serine-threonine kinase that is responsible for mitochondrial-dependent apoptosis in cardiomyocytes, possibly through Akt dephosphorylation (51,52). In turn, PTX-B-or PT9K/129G-mediated up-regulation of phosphorylated Akt would induce the transcription of antiapoptotic proteins such as Bcl-2 and Bcl-x, mainly the Bcl-x L isoform that is responsible for protection of NK cells from starvation-induced apoptosis (31,32).…”

Nestin+cells and healing the infarcted heart

“…Moreover, the transplantation of GFP-labeled folliclederived stem cells in the injured nude mouse led to the formation of fluorescent blood vessels via their differentiation to an endothelial cell phenotype (2). In addition, CNS-resident neural progenitor/stem cells, follicle-derived stem cells, and neural crest stem cells were also reported to have vascular smooth muscle differentiation capacity under the appropriate induction conditions (24,36,43,51) (Fig. 1).…”

TGF-β, Neuronal Stem Cells and Glioblastoma

“…NCSC migrate to several sites, but only under the influence of TGF-b are they able to differentiate into non-neural tissue (Wurdak et al, 2005). Calcineurin signaling may be an intermediate step induced by TGF-b which leads to adoption of smooth muscle phenotype in NCSC (Mann et al, 2004). Starting with Monc 1, a smooth muscle precursor cell line, it has been possible to generate a smooth muscle phenotype including contractile phenotype using TGF-b.…”