Precardiac deletion of Numb and Numblike reveals renewal of cardiac progenitors.
Cardiac progenitor cells (CPCs) must control their number and fate to sustain the rapid heart growth during development, yet the intrinsic factors and environment governing these processes remain unclear. Here, we show that deletion of the ancient cell-fate regulator Numb (Nb) and its homologue Numblike (Nbl) depletes CPCs in second pharyngeal arches (PA2s) and is associated with an atrophic heart. With histological, flow cytometric and functional analyses, we find that CPCs remain undifferentiated and expansive in the PA2, but differentiate into cardiac cells as they exit the arch. Tracing of Nb- and Nbl-deficient CPCs by lineage-specific mosaicism reveals that the CPCs normally populate in the PA2, but lose their expansion potential in the PA2. These findings demonstrate that Nb and Nbl are intrinsic factors crucial for the renewal of CPCs in the PA2 and that the PA2 serves as a microenvironment for their expansion.DOI: http://dx.doi.org/10.7554/eLife.02164.001.
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, United States The Knight Cardiovascular Institute, Oregon Health & Science Universtiy, Portland, United States Institute for Cell Engineering, Johns Hopkins University, Baltimore, United States.
Lincoln T
LT
Shenje
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, United States Institute for Cell Engineering, Johns Hopkins University, Baltimore, United States.
Peter
P
Andersen
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, United States Institute for Cell Engineering, Johns Hopkins University, Baltimore, United States.
Hideki
H
Uosaki
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, United States.
Laviel
L
Fernandez
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, United States Division of Cardiology, Medical University of Graz, Graz, Austria.
Peter P
PP
Rainer
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, United States Institute for Cell Engineering, Johns Hopkins University, Baltimore, United States.
Gun-Sik
GS
Cho
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, United States.
Dong-Ik
DI
Lee
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, United States.
Weimin
W
Zhong
Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia.
Richard P
RP
Harvey
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, United States.
David A
DA
Kass
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, United States Institute for Cell Engineering, Johns Hopkins University, Baltimore, United States ckwon13@jhmi.edu.
Chulan
C
Kwon
D000818:Animals; D019070:Cell Lineage; D017353:Gene Deletion; D006321:Heart / Q000196:embryology; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009030:Mosaicism; D032383:Myocytes, Cardiac / Q000166:cytology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology*
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C106293:Numb protein, mouse; C106292:Numbl protein, mouse
cardiac progenitor; heart; microenvironment; niche; numb; self-renewal