Statins impact primary embryonic mouse neural stem cell survival, cell death, and fate through distinct mechanisms

Abstract

Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthesis pathway (CBP), and are used for the prevention of cardiovascular disease. The anti-inflammatory effects of statins may also provide therapeutic benefits and have led to their use in clinical trials for preeclampsia, a pregnancy-associated inflammatory condition, despite their current classification as category X (i.e. contraindicated during pregnancy). In the developing neocortex, products of the CBP play essential roles in proliferation and differentiation of neural stem-progenitor cells (NSPCs). To understand how statins could impact the developing brain, we studied effects of pravastatin and simvastatin on primary embryonic NSPC survival, proliferation, global transcription, and cell fate in vitro. We found that statins dose dependently decrease NSPC expansion by promoting cell death and autophagy of NSPCs progressing through the G1 phase of the cell cycle. Genome-wide transcriptome analysis demonstrates an increase in expression of CBP genes following pravastatin treatment, through activation of the SREBP2 transcription factor. Co-treatment with farnesyl pyrophosphate (FPP), a CBP metabolite downstream of HMG-CoA reductase, reduces SREBP2 activation and pravastatin-induced PARP cleavage. Finally, pravastatin and simvastatin differentially alter NSPC cell fate and mRNA expression during differentiation, through a non-CBP dependent pathway.

The PI3k/Akt Pathway Is Associated With Angiogenesis, Oxidative Stress and Survival of Mesenchymal Stem Cells in Pathophysiologic Condition in Ischemia

“…At least 54 different factors and molecules were identified to be present in the secretome. Recently, the concept of MSCs secretome is believed to play an essential role in the reparative processes, because therapeutic effects of MSCs persist even if they do not engraft or differentiate into tissue-specific cells (Ferreira et al 2018). Table 1 shows MSCs secretome and its reparative and regenerative functions, which may be used in reparative mechanisms in ischemic disease.…”

Concise Review: Reduction of Adverse Cardiac Scarring Facilitates Pluripotent Stem Cell-Based Therapy for Myocardial Infarction

“…Intriguingly, cardiac gene expression and cardiomyogenesis of ESCs were enhanced by simvastatin treatment . Regarding the common use of statins in patients with heart disease and their pleiotropic effects on stem cell biology , further investigation of statins affecting survival and engraftment of PSC‐derived cardiovascular cells has great clinical implications.…”

Statins Stimulate New Myocyte Formation After Myocardial Infarction by Activating Growth and Differentiation of the Endogenous Cardiac Stem Cells

“…The potential beneficial effects of statins on stem/progenitor cells, however, have not been consistently observed for many tissue-specific stem/progenitor cells [50]. Indeed, it has been shown that statins reduce neural stem cell growth and differentiation, where they activate autophagy and apoptosis [50].…”

“…The potential beneficial effects of statins on stem/progenitor cells, however, have not been consistently observed for many tissue-specific stem/progenitor cells [50]. Indeed, it has been shown that statins reduce neural stem cell growth and differentiation, where they activate autophagy and apoptosis [50]. Additionally, treatment of mouse embryos with statins acting through the HIPPO pathway interfere with trophectoderm specification, and thereby inhibit blastocyst formation [50].…”

“…Indeed, it has been shown that statins reduce neural stem cell growth and differentiation, where they activate autophagy and apoptosis [50]. Additionally, treatment of mouse embryos with statins acting through the HIPPO pathway interfere with trophectoderm specification, and thereby inhibit blastocyst formation [50].…”