Notch1 in Bone Marrow–Derived Cells Mediates Cardiac Repair After Myocardial Infarction

Notch1 in Bone Marrow–Derived Cells Mediates Cardiac Repair After Myocardial Infarction

Yuxin Li, Yukio Hiroi, Soeun Ngoy, BS; Ryuji Okamoto, Kensuke Noma, Chao-Yung Wang, MD; Hong-Wei Wang, Qian Zhou, MD; Freddy Radtke, Ronglih Liao, PhD James K. Liao

Circulation. 2011 Published online before print February 14, 2011, doi: 10.1161/CIRCULATIONAHA.110.947531


Background The signaling mechanisms that regulate the recruitment of bone marrow (BM)–derived cells to the injured heart are not well known. Notch receptors mediate binary cell fate determination and may regulate the function of BM-derived cells. However, it is not known whether Notch1 signaling in BM-derived cells mediates cardiac repair after myocardial injury.

Methods and Results Mice with postnatal cardiac-specific deletion of Notch1 exhibit infarct size and heart function after ischemic injury that is similar to that of control mice. However, mice with global hemizygous deletion of Notch1 (N1±) developed larger infarct size and worsening heart function. When the BM of N1± mice were transplanted into wild-type (WT) mice, infarct size and heart function were worsened and neovascularization in the infarct border area was reduced compared with WT mice transplanted with WT BM. In contrast, transplantation of WT BM into N1± mice lessened the myocardial injury observed in N1± mice. Indeed, hemizygous deletion of Notch1 in BM-derived cells leads to decreased recruitment, proliferation, and survival of mesenchymal stem cells (MSC). Compared with WT MSC, injection of N1± MSC into the infarcted heart leads to increased myocardial injury whereas injection of MSC overexpressing Notch intracellular domain leads to decreased infarct size and improved cardiac function.

Conclusions These findings indicate that Notch1 signaling in BM-derived cells is critical for cardiac repair and suggest that strategies that increase Notch1 signaling in BM-derived MSC could have therapeutic benefits in patients with ischemic heart disease.

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