Gremlin2 Regulates the Differentiation and Function of Cardiac Progenitor Cells via the Notch Signaling Pathway

Abstract

Background/Aims: The transplantation of cardiac progenitor cells (CPCs) improves neovascularization and left ventricular function after myocardial infarction (MI). The bone morphogenetic protein antagonist Gremlin 2 (Grem2) is required for early cardiac development and cardiomyocyte differentiation. The present study examined the role of Grem2 in CPC differentiation and cardiac repair. Methods: To determine the role of Grem 2 during CPC differentiation, c-Kit+ CPCs were cultured in differentiation medium for different times, and Grem2, Notch1 and Jagged1 expression was determined by RT-PCR and western blotting. Short hairpin RNA was used to silence Grem2 expression, and the expression of cardiomyocyte surface markers was assessed by RT-PCR and immunofluorescence staining. In vivo experiments were performed in a mouse model of left anterior descending coronary artery ligation-induced MI. Results: CPC differentiation upregulated Grem2 expression and activated the Notch1 pathway. Grem2 knockdown inhibited cardiomyocyte differentiation, and this effect was similar to that of Notch1 pathway inhibition in vitro. Jagged1 overexpression rescued the effects of Grem2 silencing. In vivo, Grem2 silencing abolished the protective effects of CPC injection on cardiac fibrosis and function. Conclusions: Grem2 regulates CPC cardiac differentiation by modulating Notch1 signaling. Grem2 enhances the protective effect of CPCs on heart function in a mouse model of MI, suggesting its potential as the rapeutic protein for cardiac repair.

Genome‐Wide Association and Functional Studies Reveal Novel Pharmacological Mechanisms for Allopurinol

“…For GREM2 , subjects carrying the minor allele had a greater change in SUA on allopurinol and were significantly more likely to reach and maintain rheumatologist‐recommended SUA concentrations ( Figure ). GREM2 is a secreted antagonist of BMP that has been shown to play a role in cell differentiation and limit inflammation after myocardial infarctions in mice . GREM2 has been previously shown to be upregulated in glomeruli of rats with diabetic kidney disease, and dysregulation of its target, BMP, has been linked to diabetic kidney nephropathy and cardiovascular disease, suggesting a role for GREM2 in the development of common gout sequelae.…”

“…GREM2 is a secreted antagonist of BMP that has been shown to play a role in cell differentiation and limit inflammation after myocardial infarctions in mice. [21][22][23] GREM2 has been previously shown to be upregulated in glomeruli of rats with diabetic kidney disease, and dysregulation of its target, BMP, has been linked to diabetic kidney nephropathy and cardiovascular disease, 24,25 suggesting a role for GREM2 in the development of common gout sequelae. Interestingly, GREM2 has not been shown to associate with baseline SUA or gout, suggesting that its role in improving allopurinol response is pharmacologic, related to allopurinol's effects on uric acid lowering.…”

Predicting Functional Responses of Progenitor Cell Exosome Potential with Computational Modeling

“…Notch signaling plays an important role in regulating CPC differentiation [19][20][21][22]. Moreover, we have recently shown that 3D CPCs improve RV vessel density in a RVHF rat model in a Notchdependent manner [5].…”

The Role of Bone Morphogenetic Protein 7 (BMP-7) in Inflammation in Heart Diseases

“…To elaborate, embryogenesis is mediated by the activity of extracellular proteins such as chordin, noggin, cerberus, and dan family protein gremlin2. Amongst these antagonists, gremlin2 acts as the strongest BMP ligand inhibitor [112]. Alongside, chordin is involved in neural induction and mesoderm dorsalization during embryonic development.…”