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Hedgehog signaling and KLF4 contribute to maintenance of smooth muscle progenitor cells in the arterial adventitia
Author(s) -
Passman Jenna,
Dong Xiu Rong,
Hoglund Virginia J.,
Maguire Colin T.,
Chen Zhongming,
Tzima Ellie,
Majesky Mark W.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.300.1
Subject(s) - adventitia , klf4 , progenitor cell , microbiology and biotechnology , biology , sonic hedgehog , population , gene knockdown , stem cell , myocardin , anatomy , cell culture , sox2 , signal transduction , serum response factor , medicine , embryonic stem cell , transcription factor , genetics , environmental health , gene
The arterial adventitia plays important roles in growth and remodeling of the artery wall. We previously reported that sonic hedgehog (Shh) signaling is restricted to the adventitial layer of large and medium‐sized arteries in the perinatal period. Localized within this adventitial domain we found a resident population of Sca1‐positive cells (AdvSca1). Although AdvSca1 cells do not express smooth muscle cell (SMC) markers in vivo , they do express SRF and myocardin, and differentiate into SMCs when removed from the adventitia and placed in cell culture. AdvSca1 cells also express potent SRF‐dependent corepressors including KLF4 and Msx1, which may play critical roles in maintaining the SMC progenitor phenotype. We have tested this possible role of KLF4 by gain and loss of function approaches in vitro . Knockdown of KLF4 expression by siRNA results in a loss of Sca1 expression, consistent with a loss of self‐renewal potential of AdvSca1 cells. Conversely, exposure of AdvSca1 cells to KLF4 adenovirus inhibited SMC differentiation. By seven days after >80% flow reduction in a mouse carotid model, a substantially thickened neoadventitia formed that contained increased numbers of AdvSca1 cells with no evidence of SMC marker upregulation. These results suggest that resident AdvSca1 cells can proliferate in response to a stimulus for arterial remodeling, and that KLF4 plays important roles in AdvSca1 cell self‐renewal.