The role of notch 1 activation in cardiosphere derived cell differentiation

Lijuan Chen, Muhammad Ashraf, Yingjie Wang, Mi Zhou, John Zhang, Gangjian Qin, Jack Rubinstein, Neal Lee Weintraub, Yao Liang Tang

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Cardiosphere derived cells (CDC) are present in the human heart and include heterogeneous cell populations of cardiac progenitor cells, multipotent progenitors that play critical roles in the physiological and pathological turnover of heart tissue. Little is known about the molecular pathways that control the differentiation of CDC. In this study, we examined the role of Notch 1/J kappa-recombining binding protein (RBPJ) signaling, a critical cell-fate decision pathway, in CDC differentiation. We isolated CDC from mouse cardiospheres and analyzed the differentiation of transduced cells expressing the Notch1 intracellular domain (N1-ICD), the active form of Notch1, using a terminal differentiation marker polymerase chain reaction (PCR) array. We found that Notch1 primarily supported the differentiation of CDC into smooth muscle cells (SMC), as demonstrated by the upreguation of key SMC proteins, including smooth muscle myosin heavy chain (Myh11) and SM22α (Tagln), in N1-ICD expressing CDC. Conversely, genetic ablation of RBPJ in CDC diminished the expression of SMC differentiation markers, confirming that SMC differentiation CDC is dependent on RBPJ. Finally, in vivo experiments demonstrate enhanced numbers of smooth muscle actin-expressing implanted cells after an injection of N1-ICD-expressing CDC into ischemic myocardium (44±8/high power field (hpf) vs. 11±4/high power field (hpf), n=7 sections, P<0.05). Taken together, these results provide strong evidence that Notch1 promotes SMC differentiation of CDC through an RBPJ-dependent signaling pathway in vitro, which may have important implications for progenitor cell-mediated angiogenesis.

Original languageEnglish (US)
Pages (from-to)2122-2129
Number of pages8
JournalStem Cells and Development
Volume21
Issue number12
DOIs
StatePublished - Aug 10 2012
Externally publishedYes

ASJC Scopus subject areas

  • Hematology
  • Developmental Biology
  • Cell Biology

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