A critical role for heme synthesis and succinate in the regulation of pluripotent states transitions

Abstract

Using embryonic stem cells (ESCs) in regenerative medicine or in disease modeling requires a complete understanding of these cells. Two main distinct developmental states of ESCs have been stabilized in vitro, a naïve pre-implantation stage and a primed post-implantation stage. Based on two recently published CRISPR-Cas9 knockout functional screens, we show here that the exit of the naïve state is impaired upon heme biosynthesis pathway blockade, linked to the incapacity to activate MAPK- and TGFβ-dependent signaling pathways. In addition, heme synthesis inhibition promotes the acquisition of 2 cell-like cells in a heme-independent manner caused by a mitochondrial succinate accumulation and leakage out of the cell. We further demonstrate that extra-cellular succinate acts as a paracrine/autocrine signal, able to trigger the 2C-like reprogramming through the activation of its plasma membrane receptor, SUCNR1. Overall, this study unveils a new mechanism underlying the maintenance of pluripotency under the control of heme synthesis.

Heme metabolism in nonerythroid cells

“…A complete loss of Alas1 at the organismal level has proven to be embryonically lethal, suggesting the enzyme’s necessity in one or more essential biological processes, which likely includes mitochondrial biogenesis and function ( 10 ). Inhibition of heme synthesis also impairs embryonic stem cell fate indirectly as a result of succinate accumulation that occurs as a result of succinyl-CoA metabolism by ALAS1 or by reduced succinyl dehydrogenase abundance, a heme-dependent enzyme ( 51 ).…”

Succinate as a New Actor in Pluripotency and Early Development?

“…A possible role for GPR91 in the early pluripotency states had not been explored until recently, when we demonstrated that increased succinate concentrations, triggered though heme synthesis or SDH inhibition, have been shown to trigger the 2C-like cell reprogramming of mESCs in a SUCNR1-dependent manner [ 96 ]. This reveals that the activation of SUCNR1 and its downstream signals could have broad implications in early pluripotency.…”