title: Notch activation enhances lineage commitment and protective signaling in cardiac progenitor cells.
abstract: Phase I clinical trials applying autologous progenitor cells to treat heart failure have yielded promising results; however, improvement in function is modest, indicating a need to enhance cardiac stem cell reparative capacity. Notch signaling plays a crucial role in cardiac development, guiding cell fate decisions that underlie myocyte and vessel differentiation. The Notch pathway is retained in the adult cardiac stem cell niche, where level and duration of Notch signal influence proliferation and differentiation of cardiac progenitors. In this study, Notch signaling promotes growth, survival and differentiation of cardiac progenitor cells into smooth muscle lineages in vitro. Cardiac progenitor cells expressing tamoxifen-regulated intracellular Notch1 (CPCeK) are significantly larger and proliferate more slowly than control cells, exhibit elevated mTORC1 and Akt signaling, and are resistant to oxidative stress. Vascular smooth muscle and cardiomyocyte markers increase in CPCeK and are augmented further upon ligand-mediated induction of Notch signal. Paracrine signals indicative of growth, survival and differentiation increase with Notch activity, while markers of senescence are decreased. Adoptive transfer of CPCeK into infarcted mouse myocardium enhances preservation of cardiac function and reduces infarct size relative to hearts receiving control cells. Greater capillary density and proportion of vascular smooth muscle tissue in CPCeK-treated hearts indicate improved vascularization. Finally, we report a previously undescribed signaling mechanism whereby Notch activation stimulates CPC growth, survival and differentiation via mTORC1 and paracrine factor expression. Taken together, these findings suggest that regulated Notch activation potentiates the reparative capacity of CPCs in the treatment of cardiac disease.
authors.affiliation: Heart Institute, and Biology Department, SDSU Integrated Regenerative Research Institute, Life Sciences North, Room 426, 5500 Campanile Drive, San Diego, CA, 92182, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Gude
authors.forename: Eri
authors.initials: E
authors.lastname: Joyo
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Toko
authors.forename: Pearl
authors.initials: P
authors.lastname: Quijada
authors.forename: Marlo
authors.initials: M
authors.lastname: Villanueva
authors.forename: Nirmala
authors.initials: N
authors.lastname: Hariharan
authors.forename: Veronica
authors.initials: V
authors.lastname: Sacchi
authors.forename: Silvia
authors.initials: S
authors.lastname: Truffa
authors.forename: Anya
authors.initials: A
authors.lastname: Joyo
authors.forename: Mirko
authors.initials: M
authors.lastname: Voelkers
authors.forename: Roberto
authors.initials: R
authors.lastname: Alvarez
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D004195:Disease Models, Animal; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D009203:Myocardial Infarction / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000378:metabolism*; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D051880:Receptors, Notch