Abstract
Fms-like tyrosine kinase 3 (Flt3) is a regulator of hematopoietic progenitor cells and a target of tyrosine kinase inhibitors. Flt3-targeting tyrosine kinase inhibitors can have cardiovascular side effects. Flt3 and its ligand (Flt3L) are expressed in the heart, but little is known about their physiological functions. Here, we show that cardiac side population progenitor cells (SP-CPCs) from mice produce and are responsive to Flt3L. Compared with wild-type, flt3L-/- mice have less SP-CPCs with less contribution of CD45-CD34+ cells and lower expression of genes related to epithelial-to-mesenchymal transition, cardiovascular development and stem cell differentiation. Upon culturing, flt3L-/- SP-CPCs show increased proliferation and less vasculogenic commitment, whereas Akt phosphorylation is lower. Notably, proliferation and differentiation can be partially restored towards wild-type levels in the presence of alternative receptor tyrosine kinase-activating growth factors signaling through Akt. The lower vasculogenic potential of flt3L-/- SP-CPCs reflects in decreased microvascularisation and lower systolic function of flt3L-/- hearts. Thus, Flt3 regulates phenotype and function of murine SP-CPCs and contributes to cellular and molecular properties that are relevant for their cardiovasculogenic potential.
Highlights
The cardiac side population (SP) contains a pool of heterogeneous cardiac progenitor cells (CPCs) that can give rise to all cardiac lineages including cardiomyocytes, endothelial cells and vascular smooth muscle cells (Pfister et al, 2005; Noseda et al, 2015), contributing to cardiovascular homeostasis
Fms-like tyrosine kinase 3 (Flt3) is a target of Tyrosine kinase inhibitors (TKIs) used for acute myeloid leukemia treatment
We found no significant difference in the proportion of cells low in Pyronin Y expression between the wild-type and flt3L−/− SP (Figs 1B and S1B), suggesting that Flt3 does not affect the quiescence of SPCPCs
Summary
The cardiac side population (SP) contains a pool of heterogeneous CPCs that can give rise to all cardiac lineages including cardiomyocytes, endothelial cells and vascular smooth muscle cells (Pfister et al, 2005; Noseda et al, 2015), contributing to cardiovascular homeostasis. Flt activity is a determinant of the hematopoietic SP (Chu et al, 2012). These observations give rise to the hypothesis that Flt participates in the regulation of cardiac SP-CPCs. Here we describe a novel role of Flt in the regulation of abundance, composition, and functionality of the cardiac SP
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
