title: Fetal Mammalian Heart Generates a Robust Compensatory Response to Cell Loss.
abstract: BACKGROUND
  Heart development is tightly regulated by signaling events acting on a defined number of progenitor and differentiated cardiac cells. Although loss of function of these signaling pathways leads to congenital malformation, the consequences of cardiac progenitor cell or embryonic cardiomyocyte loss are less clear. In this study, we tested the hypothesis that embryonic mouse hearts exhibit a robust mechanism for regeneration after extensive cell loss.
  
  
  RESULTS
  By combining a conditional cell ablation approach with a novel blastocyst complementation strategy, we generated murine embryos that exhibit a full spectrum of cardiac progenitor cell or cardiomyocyte ablation. Remarkably, ablation of up to 60% of cardiac progenitor cells at embryonic day 7.5 was well tolerated and permitted embryo survival. Ablation of embryonic cardiomyocytes to a similar degree (50% to 60%) at embryonic day 9.0 could be fully rescued by residual myocytes with no obvious adult cardiac functional deficit. In both ablation models, an increase in cardiomyocyte proliferation rate was detected and accounted for at least some of the rapid recovery of myocardial cellularity and heart size.
  
  
  CONCLUSIONS
  Our study defines the threshold for cell loss in the embryonic mammalian heart and reveals a robust cardiomyocyte compensatory response that sustains normal fetal development.
authors.affiliation: From Stanford Cardiovascular Institute (A.C.S., K.R., K.P., A.S., A.F.X., G.L., S.M.W.), Division of Cardiovascular Medicine, Department of Medicine (A.C.S., S.M.W.), Department of Pathology (R.G.), Institute for Stem Cell Biology and Regenerative Medicine (S.M.W.), and Child Health Research Institute (S.M.W.), Stanford University School of Medicine, CA; and Division of Cardiology, Department of Medicine (A.C.S., K.R., D.P., A.R., T.C.T., M.C.E., R.F., K.D.R., M.S.-C., I.J.D.) and Department of Pathology (M.K.S.), Massachusetts General Hospital, Boston.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Sturzu
authors.affiliation: From Stanford Cardiovascular Institute (A.C.S., K.R., K.P., A.S., A.F.X., G.L., S.M.W.), Division of Cardiovascular Medicine, Department of Medicine (A.C.S., S.M.W.), Department of Pathology (R.G.), Institute for Stem Cell Biology and Regenerative Medicine (S.M.W.), and Child Health Research Institute (S.M.W.), Stanford University School of Medicine, CA; and Division of Cardiology, Department of Medicine (A.C.S., K.R., D.P., A.R., T.C.T., M.C.E., R.F., K.D.R., M.S.-C., I.J.D.) and Department of Pathology (M.K.S.), Massachusetts General Hospital, Boston.
authors.forename: Kuppusamy
authors.initials: K
authors.lastname: Rajarajan
authors.affiliation: From Stanford Cardiovascular Institute (A.C.S., K.R., K.P., A.S., A.F.X., G.L., S.M.W.), Division of Cardiovascular Medicine, Department of Medicine (A.C.S., S.M.W.), Department of Pathology (R.G.), Institute for Stem Cell Biology and Regenerative Medicine (S.M.W.), and Child Health Research Institute (S.M.W.), Stanford University School of Medicine, CA; and Division of Cardiology, Department of Medicine (A.C.S., K.R., D.P., A.R., T.C.T., M.C.E., R.F., K.D.R., M.S.-C., I.J.D.) and Department of Pathology (M.K.S.), Massachusetts General Hospital, Boston.
authors.forename: Derek
authors.initials: D
authors.lastname: Passer
authors.affiliation: From Stanford Cardiovascular Institute (A.C.S., K.R., K.P., A.S., A.F.X., G.L., S.M.W.), Division of Cardiovascular Medicine, Department of Medicine (A.C.S., S.M.W.), Department of Pathology (R.G.), Institute for Stem Cell Biology and Regenerative Medicine (S.M.W.), and Child Health Research Institute (S.M.W.), Stanford University School of Medicine, CA; and Division of Cardiology, Department of Medicine (A.C.S., K.R., D.P., A.R., T.C.T., M.C.E., R.F., K.D.R., M.S.-C., I.J.D.) and Department of Pathology (M.K.S.), Massachusetts General Hospital, Boston.
authors.forename: Karolina
authors.initials: K
authors.lastname: Plonowska
authors.affiliation: From Stanford Cardiovascular Institute (A.C.S., K.R., K.P., A.S., A.F.X., G.L., S.M.W.), Division of Cardiovascular Medicine, Department of Medicine (A.C.S., S.M.W.), Department of Pathology (R.G.), Institute for Stem Cell Biology and Regenerative Medicine (S.M.W.), and Child Health Research Institute (S.M.W.), Stanford University School of Medicine, CA; and Division of Cardiology, Department of Medicine (A.C.S., K.R., D.P., A.R., T.C.T., M.C.E., R.F., K.D.R., M.S.-C., I.J.D.) and Department of Pathology (M.K.S.), Massachusetts General Hospital, Boston.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Riley
authors.affiliation: From Stanford Cardiovascular Institute (A.C.S., K.R., K.P., A.S., A.F.X., G.L., S.M.W.), Division of Cardiovascular Medicine, Department of Medicine (A.C.S., S.M.W.), Department of Pathology (R.G.), Institute for Stem Cell Biology and Regenerative Medicine (S.M.W.), and Child Health Research Institute (S.M.W.), Stanford University School of Medicine, CA; and Division of Cardiology, Department of Medicine (A.C.S., K.R., D.P., A.R., T.C.T., M.C.E., R.F., K.D.R., M.S.-C., I.J.D.) and Department of Pathology (M.K.S.), Massachusetts General Hospital, Boston.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Tan
authors.affiliation: From Stanford Cardiovascular Institute (A.C.S., K.R., K.P., A.S., A.F.X., G.L., S.M.W.), Division of Cardiovascular Medicine, Department of Medicine (A.C.S., S.M.W.), Department of Pathology (R.G.), Institute for Stem Cell Biology and Regenerative Medicine (S.M.W.), and Child Health Research Institute (S.M.W.), Stanford University School of Medicine, CA; and Division of Cardiology, Department of Medicine (A.C.S., K.R., D.P., A.R., T.C.T., M.C.E., R.F., K.D.R., M.S.-C., I.J.D.) and Department of Pathology (M.K.S.), Massachusetts General Hospital, Boston.
authors.forename: Arun
authors.initials: A
authors.lastname: Sharma
authors.affiliation: From Stanford Cardiovascular Institute (A.C.S., K.R., K.P., A.S., A.F.X., G.L., S.M.W.), Division of Cardiovascular Medicine, Department of Medicine (A.C.S., S.M.W.), Department of Pathology (R.G.), Institute for Stem Cell Biology and Regenerative Medicine (S.M.W.), and Child Health Research Institute (S.M.W.), Stanford University School of Medicine, CA; and Division of Cardiology, Department of Medicine (A.C.S., K.R., D.P., A.R., T.C.T., M.C.E., R.F., K.D.R., M.S.-C., I.J.D.) and Department of Pathology (M.K.S.), Massachusetts General Hospital, Boston.
authors.forename: Adele F
authors.initials: AF
authors.lastname: Xu
authors.affiliation: From Stanford Cardiovascular Institute (A.C.S., K.R., K.P., A.S., A.F.X., G.L., S.M.W.), Division of Cardiovascular Medicine, Department of Medicine (A.C.S., S.M.W.), Department of Pathology (R.G.), Institute for Stem Cell Biology and Regenerative Medicine (S.M.W.), and Child Health Research Institute (S.M.W.), Stanford University School of Medicine, CA; and Division of Cardiology, Department of Medicine (A.C.S., K.R., D.P., A.R., T.C.T., M.C.E., R.F., K.D.R., M.S.-C., I.J.D.) and Department of Pathology (M.K.S.), Massachusetts General Hospital, Boston.
authors.forename: Marc C
authors.initials: MC
authors.lastname: Engels
authors.affiliation: From Stanford Cardiovascular Institute (A.C.S., K.R., K.P., A.S., A.F.X., G.L., S.M.W.), Division of Cardiovascular Medicine, Department of Medicine (A.C.S., S.M.W.), Department of Pathology (R.G.), Institute for Stem Cell Biology and Regenerative Medicine (S.M.W.), and Child Health Research Institute (S.M.W.), Stanford University School of Medicine, CA; and Division of Cardiology, Department of Medicine (A.C.S., K.R., D.P., A.R., T.C.T., M.C.E., R.F., K.D.R., M.S.-C., I.J.D.) and Department of Pathology (M.K.S.), Massachusetts General Hospital, Boston.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Feistritzer
authors.affiliation: From Stanford Cardiovascular Institute (A.C.S., K.R., K.P., A.S., A.F.X., G.L., S.M.W.), Division of Cardiovascular Medicine, Department of Medicine (A.C.S., S.M.W.), Department of Pathology (R.G.), Institute for Stem Cell Biology and Regenerative Medicine (S.M.W.), and Child Health Research Institute (S.M.W.), Stanford University School of Medicine, CA; and Division of Cardiology, Department of Medicine (A.C.S., K.R., D.P., A.R., T.C.T., M.C.E., R.F., K.D.R., M.S.-C., I.J.D.) and Department of Pathology (M.K.S.), Massachusetts General Hospital, Boston.
authors.forename: Guang
authors.initials: G
authors.lastname: Li
authors.affiliation: From Stanford Cardiovascular Institute (A.C.S., K.R., K.P., A.S., A.F.X., G.L., S.M.W.), Division of Cardiovascular Medicine, Department of Medicine (A.C.S., S.M.W.), Department of Pathology (R.G.), Institute for Stem Cell Biology and Regenerative Medicine (S.M.W.), and Child Health Research Institute (S.M.W.), Stanford University School of Medicine, CA; and Division of Cardiology, Department of Medicine (A.C.S., K.R., D.P., A.R., T.C.T., M.C.E., R.F., K.D.R., M.S.-C., I.J.D.) and Department of Pathology (M.K.S.), Massachusetts General Hospital, Boston.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Selig
authors.affiliation: From Stanford Cardiovascular Institute (A.C.S., K.R., K.P., A.S., A.F.X., G.L., S.M.W.), Division of Cardiovascular Medicine, Department of Medicine (A.C.S., S.M.W.), Department of Pathology (R.G.), Institute for Stem Cell Biology and Regenerative Medicine (S.M.W.), and Child Health Research Institute (S.M.W.), Stanford University School of Medicine, CA; and Division of Cardiology, Department of Medicine (A.C.S., K.R., D.P., A.R., T.C.T., M.C.E., R.F., K.D.R., M.S.-C., I.J.D.) and Department of Pathology (M.K.S.), Massachusetts General Hospital, Boston.
authors.forename: Richard
authors.initials: R
authors.lastname: Geissler
authors.affiliation: From Stanford Cardiovascular Institute (A.C.S., K.R., K.P., A.S., A.F.X., G.L., S.M.W.), Division of Cardiovascular Medicine, Department of Medicine (A.C.S., S.M.W.), Department of Pathology (R.G.), Institute for Stem Cell Biology and Regenerative Medicine (S.M.W.), and Child Health Research Institute (S.M.W.), Stanford University School of Medicine, CA; and Division of Cardiology, Department of Medicine (A.C.S., K.R., D.P., A.R., T.C.T., M.C.E., R.F., K.D.R., M.S.-C., I.J.D.) and Department of Pathology (M.K.S.), Massachusetts General Hospital, Boston.
authors.forename: Keston D
authors.initials: KD
authors.lastname: Robertson
authors.affiliation: From Stanford Cardiovascular Institute (A.C.S., K.R., K.P., A.S., A.F.X., G.L., S.M.W.), Division of Cardiovascular Medicine, Department of Medicine (A.C.S., S.M.W.), Department of Pathology (R.G.), Institute for Stem Cell Biology and Regenerative Medicine (S.M.W.), and Child Health Research Institute (S.M.W.), Stanford University School of Medicine, CA; and Division of Cardiology, Department of Medicine (A.C.S., K.R., D.P., A.R., T.C.T., M.C.E., R.F., K.D.R., M.S.-C., I.J.D.) and Department of Pathology (M.K.S.), Massachusetts General Hospital, Boston.
authors.forename: Marielle
authors.initials: M
authors.lastname: Scherrer-Crosbie
authors.affiliation: From Stanford Cardiovascular Institute (A.C.S., K.R., K.P., A.S., A.F.X., G.L., S.M.W.), Division of Cardiovascular Medicine, Department of Medicine (A.C.S., S.M.W.), Department of Pathology (R.G.), Institute for Stem Cell Biology and Regenerative Medicine (S.M.W.), and Child Health Research Institute (S.M.W.), Stanford University School of Medicine, CA; and Division of Cardiology, Department of Medicine (A.C.S., K.R., D.P., A.R., T.C.T., M.C.E., R.F., K.D.R., M.S.-C., I.J.D.) and Department of Pathology (M.K.S.), Massachusetts General Hospital, Boston.
authors.forename: Ibrahim J
authors.initials: IJ
authors.lastname: Domian
authors.affiliation: From Stanford Cardiovascular Institute (A.C.S., K.R., K.P., A.S., A.F.X., G.L., S.M.W.), Division of Cardiovascular Medicine, Department of Medicine (A.C.S., S.M.W.), Department of Pathology (R.G.), Institute for Stem Cell Biology and Regenerative Medicine (S.M.W.), and Child Health Research Institute (S.M.W.), Stanford University School of Medicine, CA; and Division of Cardiology, Department of Medicine (A.C.S., K.R., D.P., A.R., T.C.T., M.C.E., R.F., K.D.R., M.S.-C., I.J.D.) and Department of Pathology (M.K.S.), Massachusetts General Hospital, Boston. smwu@stanford.edu.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Wu
mesh_terms: D000818:Animals; D002452:Cell Count / Q000379:methods; D049109:Cell Proliferation / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000502:physiology*; D005318:Fetal Heart / Q000166:cytology* / Q000254:growth & development; D055879:Gene Knock-In Techniques; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000502:physiology*
keywords: heart; mice; myocytes, cardiac; regeneration; stem cells