Metabolic remodeling during somatic cell reprogramming to induced pluripotent stem cells: involvement of hypoxia-inducible factor 1

Abstract

Induced pluripotent stem cells (iPSCs) were first established from differentiated somatic cells by gene introduction of key transcription factors, OCT4, SOX2, KLF4, and c-MYC, over a decade ago. Although iPSCs can be applicable for regenerative medicine, disease modeling and drug screening, several issues associated with the utilization of iPSCs such as low reprogramming efficiency and the risk of tumorigenesis, still need to be resolved. In addition, the molecular mechanisms involved in the somatic cell reprogramming to pluripotency are yet to be elucidated. Compared with their somatic counterparts, pluripotent stem cells, including embryonic stem cells and iPSCs, exhibit a high rate of glycolysis akin to aerobic glycolysis in cancer cells. This is known as the Warburg effect and is essential for maintaining stem cell properties. This unique glycolytic metabolism in iPSCs can provide energy and drive the pentose phosphate pathway, which is the preferred pathway for rapid cell proliferation. During reprogramming, somatic cells undergo a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis trigged by a transient OXPHOS burst, resulting in the initiation and progression of reprogramming to iPSCs. Metabolic intermediates and mitochondrial functions are also involved in the epigenetic modification necessary for the process of iPSC reprogramming. Among the key regulatory molecules that have been reported to be involved in metabolic shift so far, hypoxia-inducible factor 1 (HIF1) controls the transcription of many target genes to initiate metabolic changes in the early stage and maintains glycolytic metabolism in the later phase of reprogramming. This review summarizes the current understanding of the unique metabolism of pluripotent stem cells and the metabolic shift during reprogramming, and details the relevance of HIF1 in the metabolic shift.

HIF1α/HIF2α–Sox2/Klf4 promotes the malignant progression of glioblastoma via the EGFR–PI3K/AKT signalling pathway with positive feedback under hypoxia

“…Signalling pathways regulating the pluripotency of stem cells involve transcription factors include Sox2, Oct4, Nanog, Klf4, Lin28A and Lin28B, which are reprogrammed into many tissues such as human dermal fibroblasts 17 and cardiomyocytes 18 , thus contributing to the formation of inducing pluripotent stem (iPS) cells. In addition to their roles in normal tissues, the abovementioned reprogramming factors in tumours such as colon cancer 19 , pancreatic cancer 20 , hepatocellular carcinoma 21 and lung cancer 22 induced the formation of cancer stem-like cells, and this process became remarkable under hypoxic conditions 23 , which is mainly regulated by HIF1α 24 , 25 . Therefore, we analysed the expression of the above proteins and found that only Sox2 and Klf4 were highly expressed in GBM.…”

Into Thin Air: Hypoxia Drives Metabolic and Epigenomic Deregulation of Lethal Pediatric Ependymoma

“…It is also worth noting that the hypoxiadependent, glucose-metabolism-driven remodeling of histone modification described here is reminiscent of somatic cell reprogramming toward induced pluripotent stem cells (Ishida et al, 2020). Furthermore, the hypoxia-induced upregulation of EZHIP and EPOP expression has previously been implicated in physiological epigenetic stem cell regulation (Ragazzini et al, 2019) and germ cell maturation (Beringer et al, 2016).…”

An Efficient Chemical-Defined Condition for Generation of Human Induced Pluripotent Stem Cells

“…Metabolic transition involved in somatic cell reprogramming had been examined in previous studies [35][36][37][38] . Accordingly, successful cell reprogramming requires a major metabolic shift from mitochondrial oxidative phosphorylation to glycolysis.…”