The Regeneration of Intestinal Stem Cells Is Driven by miR-29-Induced Metabolic Reprogramming

Yingying Lin, Yao Lu, Yuqi Wang, Cong Lv, Juan Chen, Yongting Luo, Heng Quan, Weiru Yu, Lining Chen, Ziyu Huang, Yanling Hao, Qingyu Wang, Qingfeng Luo, Jingyu Yan, Yixuan Li, Wei Zhang, Min Du, Jian He, Fazheng Ren, Huiyuan Guo

Engineering ›› 2024, Vol. 42 ›› Issue (11) : 39-58.

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Engineering ›› 2024, Vol. 42 ›› Issue (11) : 39-58. DOI: 10.1016/j.eng.2024.08.008
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The Regeneration of Intestinal Stem Cells Is Driven by miR-29-Induced Metabolic Reprogramming

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Abstract

Intestinal stem cells (ISCs) initiate intestinal epithelial regeneration and tumorigenesis, and they experience rapid refilling upon various injuries for epithelial repair as well as tumor reoccurrence. It is crucial to reveal the mechanism underlying such plasticity for intestinal health. Recent studies have found that metabolic pathways control stem cell fate in homeostasis, but the role of metabolism in the regeneration of ISCs after damage has not been clarified. Here, we find that in a human colorectal cancer dataset, miR-29a and b (miR-29a/b) are metabolic regulators highly associated with intestinal tumorigenesis and worse prognostic value of radiotherapy. We also show that these two microRNAs are required for intestinal stemness maintenance in mice, and their expression is induced in regenerated ISCs after irradiation injury, resulting in skewed ISC fate from differentiation towards self-renewal. This upregulation of miR-29a/b expression in ISCs leads to suppression of fatty acid oxidation (FAO) and depression of oxidative phosphorylation, which in turn controls the balance between self-renewal and differentiation of ISCs. Deletion of miR-29a/b prevents these effects and thus impairs ISC-mediated epithelial recovery. Finally, we filter the potential targets of miR-29a/b and identify Hnf4g, a transcription factor, that drives this metabolic reprogramming through regulating FAO-related enzymes. Our work discovers an important metabolic mechanism of ISC-mediated regeneration and potentially pave the way for more targeted and effective therapeutic strategies for intestinal repair as well as tumor treatment.

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MiR-29a/b / Intestinal stem cells / Regeneration / Mitochondrial oxidative phosphorylation / Fatty acid oxidation / Hnf4g

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Yingying Lin, Yao Lu, Yuqi Wang, Cong Lv, Juan Chen, Yongting Luo, Heng Quan, Weiru Yu, Lining Chen, Ziyu Huang, Yanling Hao, Qingyu Wang, Qingfeng Luo, Jingyu Yan, Yixuan Li, Wei Zhang, Min Du, Jian He, Fazheng Ren, Huiyuan Guo. The Regeneration of Intestinal Stem Cells Is Driven by miR-29-Induced Metabolic Reprogramming. Engineering, 2024, 42(11): 39‒58 https://doi.org/10.1016/j.eng.2024.08.008

References

Publishing order | Descend order by publishing year | Descend order by cited within
[1]
N. Barker, J.H. van Es, J. Kuipers, P. Kujala, M. van den Born, M. Cozijnsen, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature, 449 (7165) (2007), pp. 1003-1007
[2]
S. Alonso, O.H. Yilmaz. Nutritional regulation of intestinal stem cells. Annu Rev Nutr, 38 (2018), pp. 273-301
[3]
H. Gehart, H. Clevers. Tales from the crypt: new insights into intestinal stem cells. Nat Rev Gastroenterol Hepatol, 16 (1) (2019), pp. 19-34
[4]
R.P. Chakrabarty, N.S. Chandel. Mitochondria as signaling organelles control mammalian stem cell fate. Cell Stem Cell, 28 (3) (2021), pp. 394-408
[5]
M.J. Rodríguez-Colman, M. Schewe, M. Meerlo, E. Stigter, J. Gerrits, M. Pras-Raves, et al. Interplay between metabolic identities in the intestinal crypt supports stem cell function. Nature, 543 (7645) (2017), pp. 424-427
[6]
M.C. Ludikhuize, M. Meerlo, M.P. Gallego, D. Xanthakis, M. Burgaya Julià, T.N. Bguyen, et al. Mitochondria define intestinal stem cell differentiation downstream of a FOXO/Notch Axis. Cell Metab, 32 (5) (2020), pp. 889-900
[7]
D. Wang, J. Odle, Y.L. Liu. Metabolic regulation of intestinal stem cell homeostasis. Trends Cell Biol, 31 (5) (2021), pp. 325-327
[8]
M.M. Mihaylova, C.W. Cheng, A.Q. Cao, S. Tripathi, M.D. Mana, K.E. Bauer-Rowe, et al. Fasting activates fatty acid oxidation to enhance intestinal stem cell function during homeostasis and aging. Cell Stem Cell, 22 (5) (2018), pp. 769-778
[9]
M.D. Mana, A.M. Hussey, C.N. Tzouanas, S. Imada, Y. Barrera Millan, D. Bahceci, et al. High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity. Cell Rep, 35 (10) (2021), Article 109212
[10]
L. Chen, R.P. Vasoya, N.H. Toke, A. Parthasarathy, S. Luo, E. Chiles, et al. HNF 4 regulates fatty acid oxidation and is required for renewal of intestinal stem cells in mice. Gastroenterology, 158 (4) (2020), pp. 985-999
[11]
R.R. Stine, A.P. Sakers, T. TeSlaa, M. Kissig, Z.E. Stine, C.W. Kwon, et al. PRDM16 maintains homeostasis of the intestinal epithelium by controlling region-specific metabolism. Cell Stem Cell, 25 (6) (2019), pp. 830-845
[12]
Y.J. Gao, Y. Yan, S. Tripathi, N. Pentinmikko, A. Amaral, P. Päivinen, et al. LKB 1 represses ATOH1 via PDK4 and energy metabolism and regulates intestinal stem cell fate. Gastroenterology, 158 (5) (2020), pp. 1389-1401
[13]
L. Zipper, S. Batchu, N.H. Kaya, Z.A. Antonello, T. Reiff. The microRNA miR-277 controls physiology and pathology of the adult drosophila midgut by regulating the expression of fatty acid beta-oxidation-related genes in intestinal stem cells. Metabolites, 12 (4) (2022), p. 315
[14]
Y.H. Tian, X.H. Ma, C. Lv, X.L. Sheng, X. Li, R. Zhao, et al. Stress responsive miR-31 is a major modulator of mouse intestinal stem cells during regeneration and tumorigenesis. eLife, 6 (2017), p. 29538
[15]
Y.H. Tian, J.Z. Xu, Y. Li, R. Zhao, S.J. Du, C. Lv, et al. MicroRNA-31 reduces inflammatory signaling and promotes regeneration in colon epithelium, and delivery of mimics in microspheres reduces colitis in mice. Gastroenterology, 156 (8) (2019), pp. 2281-2296
[16]
X.L. Wang, Y. He, B. Mackowiak, B. Gao. MicroRNAs as regulators, biomarkers and therapeutic targets in liver diseases. Gut, 70 (4) (2021), pp. 784-795
[17]
J.J. Kwon, T.D. Factora, S. Dey, J. Kota. A systematic review of miR-29 in cancer. Mol Ther Oncolytics, 12 (2019), pp. 173-194
[18]
H.Y. Lin, F.S. Wang, Y.L. Yang, Y.H. Huang. MicroRNA-29a suppresses CD36 to ameliorate high fat diet-induced steatohepatitis and liver fibrosis in mice. Cells, 8 (10) (2019), p. 1298
[19]
M.E. Widlansky, D.M. Jensen, J.L. Wang, Y. Liu, A.M. Geurts, A.J. Kriegel, et al. MiR-29 contributes to normal endothelial function and can restore it in cardiometabolic disorders. EMBO Mol Med, 10 (3) (2018), p. 8046
[20]
O. Brain, B.M.J. Owens, T. Pichulik, P. Allan, E. Khatamzas, A. Leslie, et al. The intracellular sensor NOD 2 induces microRNA-29 expression in human dendritic cells to limit iL-23 release. Immunity, 39 (3) (2013), pp. 521-536
[21]
T. Fukata, T. Mizushima, J. Nishimura, D. Okuzaki, X. Wu, H. Hirose, et al. The supercarbonate apatite-microRNA complex inhibits dextran sodium sulfate-induced colitis. Mol Ther Nucleic Acids, 12 (2018), pp. 658-671
[22]
S. Dey, L.M. Udari, P. RiveraHernandez, J.J. Kwon, B. Willis, J.J. Easler, et al. Loss of miR-29a/b 1 promotes inflammation and fibrosis in acute pancreatitis. JCI Insight, 6 (19) (2021), Article 149539
[23]
Y.H. Zhu, W. Wang, T.L. Yuan, L.L. Fu, L.A. Zhou, G. Lin, et al. MicroRNA-29a mediates the impairment of intestinal epithelial integrity induced by intrauterine growth restriction in pig. Am J Physiol Gastrointest Liver Physiol, 312 (5) (2017), pp. G434-G442
[24]
L. Xiao, J.N. Rao, T.T. Zou, L. Liu, S. Cao, J.L. Martindale, et al. MiR-29b represses intestinal mucosal growth by inhibiting translation of cyclin-dependent kinase 2. Mol Biol Cell, 24 (19) (2013), pp. 3038-3046
[25]
M. Ouyang, W.J. Su, L. Xiao, J.N. Rao, L.P. Jiang, Y. Li, et al. Modulation by miR-29b of intestinal epithelium homoeostasis through the repression of menin translation. Biochem J, 465 (2) (2015), pp. 315-323
[26]
Y.W. Li, G. Chen, J.Y. Wang, T.T. Zou, L. Liu, L. Xiao, et al. Post-transcriptional regulation of Wnt co-receptor LRP6 and RNA-binding protein HuR by miR-29b in intestinal epithelial cells. Biochem J, 473 (11) (2016), pp. 1641-1649
[27]
Y.Y. Lin, Y. Lu, Z.Y. Huang, Y.Q. Wang, S.J. Song, Y. Luo, et al. Milk-derived small extracellular vesicles promote recovery of intestinal damage by accelerating intestinal stem cell-mediated epithelial regeneration. Mol Nutr Food Res, 66 (11) (2022), p. 2100551
[28]
T. Sato, R.G. Vries, H.J. Snippert, M. van de Wetering, N. Barker, D.E. Stange, et al. Single Lgr 5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature, 459 (7244) (2009), pp. 262-265
[29]
M.C. Ludikhuize, M. Meerlo, B.M.T. Burgering, M.J. Rodríguez Colman. Protocol to profile the bioenergetics of organoids using seahorse. STAR Protocols., 2 (1) (2021), Article 100386
[30]
A. Ayyaz, S. Kumar, B. Sangiorgi, B. Ghoshal, J. Gosio, S. Ouladan, et al. Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell. Nature, 569 (7754) (2019), pp. 121-125
[31]
E.D. Bankaitis, A. Ha, C.J. Kuo, S.T. Magness. Reserve stem cells in intestinal homeostasis and injury. Gastroenterology, 155 (5) (2018), pp. 1348-1361
[32]
K. Murata, U. Jadhav, S. Madha, J. van Es, J. Dean, A. Cavazza, et al. Ascl2-dependent cell dedifferentiation drives regeneration of ablated intestinal stem cells. Cell Stem Cell, 26 (3) (2020), pp. 377-390
[33]
S.J.A. Buczacki, H.I. Zecchini, A.M. Nicholson, R. Russell, L. Vermeulen, R. Kemp, et al. Intestinal label-retaining cells are secretory precursors expressing Lgr5. Nature, 495 (7439) (2013), pp. 65-69
[34]
M.F. de Sousae, F.J. de Sauvage. Cellular plasticity in intestinal homeostasis and disease. Cell Stem Cell, 24 (1) (2019), pp. 54-64
[35]
J.H. van Es, T. Sato, M. van de Wetering, A. Lyubimova, A.N. Yee Nee, A. Gregorieff, et al. Dll1(+) secretory progenitor cells revert to stem cells upon crypt damage. Nat Cell Biol, 14 (10) (2012), pp. 1099-1104
[36]
K.S. Yan, O. Gevaert, G.X.Y. Zheng, B. Anchang, C.S. Probert, K.A. Larkin, et al. Intestinal enteroendocrine lineage cells possess homeostatic and injury-inducible stem cell activity. Cell Stem Cell, 21 (1) (2017), pp. 78-90
[37]
G. Calibasi-Kocal, O. Mashinchian, Y. Basbinar, E. Ellidokuz, C.W. Cheng, Ö.H. Yilmaz. Nutritional control of intestinal stem cells in homeostasis and tumorigenesis. Trends Endocrinol Metab, 32 (1) (2021), pp. 20-35
[38]
J. Kalucka, R. Missiaen, M. Georgiadou, S. Schoors, C. Lange, K. De Bock, et al. Metabolic control of the cell cycle. Cell Cycle, 14 (21) (2015), pp. 3379-3388
[39]
D. Roy, G.Y. Sheng, S. Herve, E. Carvalho, A. Mahanty, S. Yuan, et al. Interplay between cancer cell cycle and metabolism: challenges, targets and therapeutic opportunities. Biomed Pharmacother, 89 (2017), pp. 288-296
[40]
R. Nusse, H. Clevers. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell, 169 (6) (2017), pp. 985-999
[41]
J.H. Van Es, M.E. van Gijn, O. Riccio, M. van den Born, M. Vooijs, H. Begthel, et al. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature, 435 (7044) (2005), pp. 959-963
[42]
L. Pellegrinet, V. Rodilla, Z.Y. Liu, S.A. Chen, U. Koch, L. Espinosa, et al. Dll1- and Dll4-mediated notch signaling are required for homeostasis of intestinal stem cells. Gastroenterology, 140 (4) (2011), pp. 1230-1240
[43]
K.L. VanDussen, A.J. Carulli, T.M. Keeley, S.R. Patel, B.J. Puthoff, S.T. Magness, et al. Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells. Development, 139 (3) (2012), pp. 488-497
[44]
J.C. Schell, D.R. Wisidagama, C. Bensard, H.L. Zhao, P. Wei, J. Tanner, et al. Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism. Nat Cell Biol, 19 (9) (2017), pp. 1027-1036
[45]
C.L. Bensard, D.R. Wisidagama, K.A. Olson, J.A. Berg, N.M. Krah, J.C. Schell, et al. Regulation of tumor initiation by the mitochondrial pyruvate carrier. Cell Metab, 31 (2) (2020), pp. 284-300
[46]
L. van Landeghem, M.A. Santoro, A.E. Krebs, A.T. Mah, J.J. Dehmer, A.D. Gracz, et al. Activation of two distinct Sox9-EGFP-expressing intestinal stem cell populations during crypt regeneration after irradiation. Am J Physiol Gastrointest Liver Physiol, 302 (10) (2012), pp. G1111-G1132
[47]
S. Beyaz, C.R. Chung, H.W. Mou, K.E. Bauer-Rowe, M.E. Xifaras, I. Egin, et al. Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis. Cell Stem Cell, 28 (2021), pp. 1922-1935
[48]
C.A. Richmond, M.S. Shah, L.T. Deary, D.C. Trotier, H. Thomas, D.M. Ambruzs, et al. Dormant intestinal stem cells are regulated by PTEN and nutritional status. Cell Rep, 13 (11) (2015), pp. 2403-2411
[49]
C.W. Cheng, M. Biton, A.L. Haber, N. Gunduz, G. Eng, L.T. Gaynor, et al. Ketone body signaling mediates intestinal stem cell homeostasis and adaptation to diet. Cell, 178 (5) (2019), pp. 1115-1131
[50]
N. Gebert, C.W. Cheng, J.M. Kirkpatrick, D. Di Fraia, J.N. Yun, P. Schädel, et al. Region-specific proteome changes of the intestinal epithelium during aging and dietary restriction. Cell Rep, 31 (4) (2020), Article 107565
[51]
Q.D. Wang, Y.N. Zhou, P. Rychahou, T.W.M. Fan, A.N. Lane, H.L. Weiss, et al. Ketogenesis contributes to intestinal cell differentiation. Cell Death Differ, 24 (3) (2017), pp. 458-468
[52]
O. Dmitrieva-Posocco, A.C. Wong, P. Lundgren, A.M. Golos, H.C. Descamps, L. Dohnalová, et al. β-hydroxybutyrate suppresses colorectal cancer. Nature, 605 (7908) (2022), pp. 160-165
[53]
B. Pereira, A.L. Amaral, A. Dias, N. Mendes, V. Muncan, A.R. Silva, et al. MEX3A regulates Lgr5(+) stem cell maintenance in the developing intestinal epithelium. EMBO Rep, 21 (4) (2020), p. 48938
[54]
O.H. Yilmaz, P. Katajisto, D.W. Lamming, Y. Gultekin, K.E. Bauer-Rowe, S. Sengupta, et al. mTORC 1 in the paneth cell niche couples intestinal stem-cell function to calorie intake. Nature, 486 (7404) (2012), pp. 490-495
[55]
M. Igarashi, L. Guarente. mTORC1 and SIRT1 cooperate to foster expansion of gut adult stem cells during calorie restriction. Cell, 166 (2) (2016), pp. 436-450
[56]
R.G.H. Lindeboom, L. van Voorthuijsen, K.C. Oost, M.J. Rodriguez-Colman, M.V. Luna-Velez, C. Furlan, et al. Integrative multi-omics analysis of intestinal organoid differentiation. Mol Syst Biol, 14 (6) (2018), p. 8227
[57]
L. Chen, N.H. Toke, S. Luo, R.P. Vasoya, R.L. Fullem, A. Parthasarathy, et al. A reinforcing HNF4-SMAD 4 feed-forward module stabilizes enterocyte identity. Nat Genet, 51 (5) (2019), pp. 777-785
[58]
J.H. Shin, J. Jeong, J. Choi, J. Lim, R.K. Dinesh, J. Braverman, et al. Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF 4 alpha 1. iScience, 24 (5) (2021), Article 102411
[59]
P.S. Montenegro-Miranda, J.H.M. van der Meer, C. Jones, S. Meisner, J.L.M. Vermeulen, J. Koster, et al. A novel organoid model of damage and repair identifies HNF 4 alpha as a critical regulator of intestinal epithelial regeneration. Cell Mol Gastroenterol Hepatol, 10 (2) (2020), pp. 209-223
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