Abstract
Background: The Hippo pathway can regulate the fate and metabolic function of stem/progenitor cells through a kinase cascade that impinges on the transcription of growth-regulatory genes. This study investigates the role of HCLS-associated protein X-1 (HAX1) on the Hippo pathway with a goal of enhancing the therapeutic effects of sca1 + cardiac stem cells (CSCs sca1+ ) in mouse ischemic hearts. Methods and Results: Western Blot assessment showed that phosphorylation levels of Yes-associated protein (Yap), the terminal effector of Hippo pathway, was increased in CSCs sca1+ when endogenous HAX1 gene expression was silenced, whereas lentiviral over-expression of HAX1 maintained Yap activation by inhibiting its phosphorylation at Serine-397. ImageStream flow cytometry was then used to observe the enhanced nuclear translocation of Yap. Hypoxia exposure promoted this translocation to a greater extent in HAX1-overexpressing CSCs sca1+ (CSCs HAX1 ) than non-encoding DNA sequence-transduced CSCs sca1+ (CSCs Null ) ( Fig 1A ). HAX-1 over-expression enhanced cardioprotective molecular mechanisms by restraining the dissipation of mitochondrial membrane potential (Fig 1B) , inhibiting endoplasmic reticulum stress response, promoting HIF-1α expression, and upregulating anti-fibrotic gene expression in CSCs sca1+ response to hypoxia injury. Echocardiography and histological assessment demonstrated that contractile function was significantly improved and cardiac fibrosis was decreased in ischemic mouse hearts post engraftment of CSCs HAX1 when compared with those of the CSCs Null -transplanted group ( Fig 1C ). Conclusion: HAX1 over-expression can regulate Hippo signal and promote nuclear translocation of Yap, upregulating intrinsic protective mechanisms of CSCs sca1+ . This results in greater improvement of cardiac function in ischemic hearts post transplantation of HAX1 over-expressing CSCs sca1+ .
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
