The HH-GLI2-CKS1B network regulates the proliferation-to-maturation transition of cardiomyocytes.
Stem Cells Transl Med
; 13(7): 678-692, 2024 Jul 15.
Article
en En
| MEDLINE
| ID: mdl-38761090
ABSTRACT
Cardiomyocyte (CM) proliferation and maturation are highly linked processes, however, the extent to which these processes are controlled by a single signaling axis is unclear. Here, we show the previously undescribed role of Hedgehog (HH)-GLI2-CKS1B cascade in regulation of the toggle between CM proliferation and maturation. Here we show downregulation of GLI-signaling in adult human CM, adult murine CM, and in late-stage hiPSC-CM leading to their maturation. In early-stage hiPSC-CM, inhibition of HH- or GLI-proteins enhanced CM maturation with increased maturation indices, increased calcium handling, and transcriptome. Mechanistically, we identified CKS1B, as a new effector of GLI2 in CMs. GLI2 binds the CKS1B promoter to regulate its expression. CKS1B overexpression in late-stage hiPSC-CMs led to increased proliferation with loss of maturation in CMs. Next, analysis of datasets of patients with heart disease showed a significant enrichment of GLI2-signaling in patients with ischemic heart failure (HF) or dilated-cardiomyopathy (DCM) disease, indicating operational GLI2-signaling in the stressed heart. Thus, the Hh-GLI2-CKS1B axis regulates the proliferation-maturation transition and provides targets to enhance cardiac tissue engineering and regenerative therapies.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Miocitos Cardíacos
/
Proliferación Celular
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Proteína Gli2 con Dedos de Zinc
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Stem Cells Transl Med
/
Stem cells transl. med. (Online)
/
Stem cells translational medicine (Online)
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos