O-cyclic phytosphingosine-1-phosphate stimulates HIF1α-dependent glycolytic reprogramming to enhance the therapeutic potential of mesenchymal stem cells

Hyun Jik Lee; Young Hyun Jung; Gee Euhn Choi; Jun Sung Kim; Chang Woo Chae; Jae Ryong Lim; Seo Yihl Kim; Joo Eun Lee; Min Chul Park; Jee Hyeon Yoon; Myeong Jun Choi; Kye-Seong Kim; Ho Jae Han

doi:10.1038/s41419-019-1823-7

O-cyclic phytosphingosine-1-phosphate stimulates HIF1α-dependent glycolytic reprogramming to enhance the therapeutic potential of mesenchymal stem cells

Cell Death Dis. 2019 Aug 5;10(8):590. doi: 10.1038/s41419-019-1823-7.

Authors

Affiliations

¹ Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, Seoul National University, Seoul, 08826, Republic of Korea.
² Axcesobiopharma, 268 Hakuiro, Dongan-gu, Anyang, 14056, Republic of Korea.
³ Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea.
⁴ Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, Seoul National University, Seoul, 08826, Republic of Korea. [email protected].

Abstract

O-cyclic phytosphingosine-1-phosphate (cP1P) is a novel chemically synthesized sphingosine metabolite derived from phytosphingosine-1-phosphate. Although structurally similar to sphingosine-1-phosphate (S1P), its biological properties in stem cells remain to be reported. We investigated the effect of cP1P on the therapeutic potential of mesenchymal stem cells (MSCs) and their regulatory mechanism. We found that, under hypoxia, cP1P suppressed MSC mitochondrial dysfunction and apoptosis. Metabolic data revealed that cP1P stimulated glycolysis via the upregulation of glycolysis-related genes. cP1P-induced hypoxia-inducible factor 1 alpha (HIF1α) plays a key role for MSC glycolytic reprogramming and transplantation efficacy. The intracellular calcium-dependent PKCα/mammalian target of the rapamycin (mTOR) signaling pathway triggered by cP1P regulated HIF1α translation via S6K1, which is critical for HIF1 activation. Furthermore, the cP1P-activated mTOR pathway induced bicaudal D homolog 1 expression, leading to HIF1α nuclear translocation. In conclusion, cP1P enhances the therapeutic potential of MSC through mTOR-dependent HIF1α translation and nuclear translocation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Cell Hypoxia
Cell Survival / drug effects
Cell Survival / genetics
Cells, Cultured
Fetal Blood / cytology
Glycolysis / drug effects*
Glycolysis / genetics
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Lysophospholipids / pharmacology
Male
Membrane Potential, Mitochondrial / drug effects
Mesenchymal Stem Cell Transplantation
Mesenchymal Stem Cells / drug effects*
Mesenchymal Stem Cells / metabolism*
Mice
Mice, Inbred ICR
Mitochondria / drug effects
Mitochondria / metabolism
Protein Biosynthesis / drug effects
Protein Biosynthesis / genetics
Protein Transport
Reactive Oxygen Species / metabolism
Signal Transduction / drug effects
Sphingosine / analogs & derivatives*
Sphingosine / pharmacology
TOR Serine-Threonine Kinases / metabolism
Transfection
Up-Regulation / drug effects

Substances

HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
Lysophospholipids
Reactive Oxygen Species
phytosphingosine-1-phosphate
sphingosine 1-phosphate
MTOR protein, human
TOR Serine-Threonine Kinases
Sphingosine