β1-integrin is a cell-autonomous factor mediating the Numb pathway for cardiac progenitor maintenance

Abstract

Proper control of multipotent/stem cell number and fate is essential for ensuing organ formation during development. β1-integrin, a subfamily of cell surface receptors, has a conserved role in maintenance of multipotent/stem cells, including renal progenitor cells, follicle stem cells, epidermal stem cells and neural stem cells. However, it remains unclear whether β1-integrin has a role in cardiac progenitor cell (CPC) development. Here we show that a mesodermal deletion of β1-integrin decreases Isl1⁺ cell number in the second pharyngeal arch (PA2), where CPCs undergo renewal and expansion. Mesp1 lineage-specific mosaicism revealed that β1-integrin-deleted Isl1⁺ cells do not proliferate in the PA2. Consistently, β1-integrin-deleted Isl1⁺ CPCs failed to expand in vitro, independent of PA2 cells. β1-integrin co-localized and physically associated with Numb, a crucial regulator of CPC renewal and expansion. Importantly, Numb/Numbl-deleted CPCs showed dramatic reduction in β1-integrin levels. These findings suggest that β1-integrin is a key mediator of the Numb pathway in CPC maintenance.

Keywords: Cardiac development; Cardiac progenitor expansion; ES/iPS cells; Numb/Numbl; Second heart field; β1-integrin.