Notch activation enhances lineage commitment and protective signaling in cardiac progenitor cells
| Autor: | Mirko Voelkers, Roberto Alvarez, Silvia Truffa, Anya Y. Joyo, Natalie Gude, Pearl Quijada, Haruhiro Toko, Mark A. Sussman, Veronica Sacchi, Marlo Villanueva, Nirmala Hariharan, Eri Joyo |
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| Rok vydání: | 2015 |
| Předmět: |
Cardiac function curve
medicine.medical_specialty Vascular smooth muscle Physiology Immunoblotting Cell- and Tissue-Based Therapy Myocardial Infarction Notch signaling pathway mTORC1 Biology Real-Time Polymerase Chain Reaction Article Mice Paracrine signalling Physiology (medical) Internal medicine medicine Animals Myocyte Cell Lineage Myocytes Cardiac Progenitor cell Receptors Notch Stem Cells Cell Differentiation Adoptive Transfer Immunohistochemistry Cell biology Disease Models Animal Endocrinology Hes3 signaling axis Cardiology and Cardiovascular Medicine Stem Cell Transplantation |
| Zdroj: | Basic Research in Cardiology. 110 |
| ISSN: | 1435-1803 0300-8428 |
| DOI: | 10.1007/s00395-015-0488-3 |
| Popis: | 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 Notchl (CPCeK) are significantly larger and proliferate more slowly than control cells, exhibit elevated mTORCl 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 mTORCl 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. |
| Databáze: | OpenAIRE |
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