TY - JOUR
T1 - Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet
AU - Cheng, Chia-Wei
AU - Biton, Moshe
AU - Haber, Adam L.
AU - Gunduz, Nuray
AU - Eng, George
AU - Gaynor, Liam T.
AU - Tripathi, Surya
AU - Calibasi-Koca, Gizem
AU - Rickelt, Steffen
AU - Butty, Vincent L.
AU - Moreno-Serrano, Marta
AU - Iqbal, Ameena M.
AU - Bauer-Rowe, Khristian E.
AU - Imada, Shinya
AU - Ulutas, Mehmet Sefa
AU - Mylonas, Constantine
AU - Whary, Mark T.
AU - Levine, Stuart S.
AU - Basbinar, Yasemin
AU - Hynes, Richard O.
AU - Mino-Kenudson, Mari
AU - Deshpande, Vikram
AU - Boyer, Laurie A.
AU - Fox, James G.
AU - Terranova, Christopher
AU - Rai, Kunal
AU - Piwnica-Worms, Helen
AU - Mihaylova, Maria M.
AU - Regev, Aviv
AU - Yilmaz, Omer H.
N1 - We thank Fang Wang for providing βOHB oligomers. We thank Dr. Julien Sage and Dr. Spyros Artavanis-Tsakonas for the generous gift of Hes1-GFP reporter mice. We thank Sven Holder for histology support, the Whitehead Institute Metabolite profiling core facility, and the Koch Institute Flow Cytometry, Histology, and ES Cell and Transgenics core facilities. We thank Leah Bury for illustration assistance, members of the Yilmaz laboratory for discussions, and Kerry Kelley for laboratory management. Ö.H.Y. is supported by NIH R00 AG045144, R01CA211184, R01CA034992, and U54CA224068; a V Foundation V scholar award; a Sidney Kimmel scholar award; a Pew-Stewart Trust scholar award; the Kathy and Curt Marble Cancer Research Fund; a Bridge grant; the American Federation of Aging Research (AFAR); and the MIT Stem Cell Initiative through Fondation MIT. C.W.C. is supported by a Ludwig postdoctoral fellowship and a Helen Hay Whitney postdoctoral fellowship. N.G is supported by a TUBITAK-BIDEB 2214-A fellowship. G.C.-K. is supported by a TUBITAK 2219 international postdoctoral research fellowship. We thank the members of The Hope Babette Tang (1983) Histology Facility at the Koch Institute. S.R. was supported by a postdoctoral fellowship from the MIT Ludwig Center for Molecular Oncology Research, NIH grant U54-CA163109, and the Howard Hughes Medical Institute (to R.O.H.). A.R. is supported by the Klarman Cell Observatory and HHMI. M.M.M. is supported by NIH R00 AG054760. A.R. is a SAB member of Thermo Fisher Scientific, Driver Group, and Syros Pharmaceuticals and a co-founder of Celsius Therapeutics. We would like to thank Kerry Kelly for excellent lab management. Author Contribution C.-W.C. conceived, designed, performed, interpreted all of the experiments and wrote the manuscript with Ö.H.Y. M.B. performed single-cell RNA-seq, and A.L.H. conducted statistical analysis with support from A.R. C.T. performed ChIP sequencing and data analysis with support from H.P.-W. and K.R. N.G., S.T., M.M., A.M.I., K.E.B.-R., S.I., and M.S.U. performed Hmgcs2 deletion and dietary experiments. G.E. designed and prepared modified βOHB for in vivo experiments. L.T.G. performed Atoh1 intestinal deletion experiments and participated in experimental design and data analysis. C.M. and L.A.B. assisted with the data analysis. G.C.-K. and S.R. performed histopathological examination and provided diagnostic information with support from Y.B., M.M.-K., V.D., and R.O.H. M.M.M. contributed to gene expression profiling and to the development of crypt metabolomic assays for FAO analysis. M.T.W. provided animal research facility support and assisted in the design and interpretation of experiments with support from J.G.F. V.L.B. performed bioinformatics analysis with support from S.S.L. All of the authors assisted in the interpretation of the experiments and the writing of the paper.
PY - 2019/8/22
Y1 - 2019/8/22
N2 - Little is known about how metabolites couple tissue-specific stem cell function with physiology. Here we show that, in the mammalian small intestine, the expression of Hmgcs2 (3-hydroxy-3-methylglutaryl-CoA synthetase 2), the gene encoding the rate-limiting enzyme in the production of ketone bodies, including beta-hydroxybutyrate (βOHB), distinguishes self-renewing Lgr5 + stem cells (ISCs) from differentiated cell types. Hmgcs2 loss depletes βOHB levels in Lgr5 + ISCs and skews their differentiation toward secretory cell fates, which can be rescued by exogenous βOHB and class I histone deacetylase (HDAC) inhibitor treatment. Mechanistically, βOHB acts by inhibiting HDACs to reinforce Notch signaling, instructing ISC self-renewal and lineage decisions. Notably, although a high-fat ketogenic diet elevates ISC function and post-injury regeneration through βOHB-mediated Notch signaling, a glucose-supplemented diet has the opposite effects. These findings reveal how control of βOHB-activated signaling in ISCs by diet helps to fine-tune stem cell adaptation in homeostasis and injury. Ketone body metabolites inform intestinal stem cell decisions in response to diverse diets.
AB - Little is known about how metabolites couple tissue-specific stem cell function with physiology. Here we show that, in the mammalian small intestine, the expression of Hmgcs2 (3-hydroxy-3-methylglutaryl-CoA synthetase 2), the gene encoding the rate-limiting enzyme in the production of ketone bodies, including beta-hydroxybutyrate (βOHB), distinguishes self-renewing Lgr5 + stem cells (ISCs) from differentiated cell types. Hmgcs2 loss depletes βOHB levels in Lgr5 + ISCs and skews their differentiation toward secretory cell fates, which can be rescued by exogenous βOHB and class I histone deacetylase (HDAC) inhibitor treatment. Mechanistically, βOHB acts by inhibiting HDACs to reinforce Notch signaling, instructing ISC self-renewal and lineage decisions. Notably, although a high-fat ketogenic diet elevates ISC function and post-injury regeneration through βOHB-mediated Notch signaling, a glucose-supplemented diet has the opposite effects. These findings reveal how control of βOHB-activated signaling in ISCs by diet helps to fine-tune stem cell adaptation in homeostasis and injury. Ketone body metabolites inform intestinal stem cell decisions in response to diverse diets.
UR - http://www.scopus.com/inward/record.url?scp=85070720035&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2019.07.048
DO - 10.1016/j.cell.2019.07.048
M3 - مقالة
SN - 0092-8674
VL - 178
SP - 1115
EP - 1131
JO - Cell
JF - Cell
IS - 5
ER -