RT Journal Article
SR Electronic
T1 Fms-like tyrosine kinase 3 is a regulator of the cardiac side population in mice
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202101112
DO 10.26508/lsa.202101112
VO 5
IS 3
A1 Della Verde, Giacomo
A1 Mochizuki, Michika
A1 Lorenz, Vera
A1 Roux, Julien
A1 Xu, Lifen
A1 Ramin-Wright, Leandra
A1 Pfister, Otmar
A1 Kuster, Gabriela M
YR 2022
UL https://www.life-science-alliance.org/content/5/3/e202101112.abstract
AB 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.