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Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism

Abstract

Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells.

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Figure 1: MPC expression is low in intestinal stem cells and increases following differentiation.
Figure 2: Drosophila MPC regulates intestinal stem cell proliferation.
Figure 3: MPC deletion in the Lgr5-EGFP compartment increases intestinal stem cell maintenance and proliferation.
Figure 4: In vitro loss of the MPC increases stem cell function and organoid formation.
Figure 5: In vitro loss of the MPC alters protein expression and metabolism.
Figure 6: In vitro inhibition of MPC activity increases organoid formation.

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Acknowledgements

We thank B. Edgar (University of Utah, USA) for stocks and reagents, C. Micchelli (Washington University School of Medicine, USA) for providing the Notch RNAi line, K. Beebe for helpful advice and comments on the Drosophila intestinal studies, G. Lam for establishing the Drosophila MPC overexpression strain, O. Yilmaz and D. Sabatini for assistance and insight into intestinal stem cell metabolism, D. Tantin for critiques and comments, members of the Rutter laboratory for assistance and advice, J. O’Shea, R. Orbus and C. DeHeer for assistance with NanoString, W. Swiatek for mouse assistance, ARUP Institute for Clinical and Experimental Pathology, and S. R. Tripp and E. Hammond for histology; L. Nikolova at the University of Utah Electron Microscopy Core Laboratory performed electron microscopy; mass spectrometry analysis was performed at the Mass Spectrometry and Proteomics Core Facility at the University of Utah. Mass spectrometry equipment was obtained through NCRR Shared Instrumentation Grant no. 1 S10 RR020883-01, 1 S10 RR025532-01A1, NIH 1 S10OD021505-01 (J.E.C.) and the Diabetes and Metabolism Center at the University of Utah. This study was conducted with support from the Biorepository and Molecular Pathology Shared Resource supported by the Cancer Center Support Grant awarded to the Huntsman Cancer Institute by the National Cancer Institute of the National Institutes of Health. Nanostring transcript analysis utilized the Molecular Diagnostics Section of the Biorepository and Molecular Pathology Shared Resource and was supported by the National Cancer Institute of the National Institutes of Health under Award Number P30CA042014 (the content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH). J. Marvin at the University of Utah Flow Cytometry Facility carried out flow sorting (National Cancer Institute through Award Number 5P30CA042014-24, National Center for Research Resources of the National Institutes of Health under Award Number 1S10RR026802-01). Funding was also provided by HHMI (J.R.), Treadwell (J.R.) and RO1GM094232 (to J.R. and C.S.T.). J.C.S. was supported by an NIH Developmental Biology Training Grant (5T32 HD07491) and a University of Utah Graduate Research Fellowship. D.R.W. was supported by a University of Utah Graduate Research Fellowship.

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Conceptualization, J.C.S., D.R.W., C.S.T. and J.R.; methodology, J.C.S., D.R.W., C.B., H.Z., P.W., J.T., A.F., J.M., L.K.S., C.S.E., K.A.O., D.D., P.K., M.P.B., D.Y.L., J.E.C., H.R.C., W.E.L., C.S.T. and J.R.; investigation, J.C.S., D.R.W., C.B., H.Z., P.W., J.T., A.F., J.M., L.K.S., C.S.E., R.M., D.D. and P.K.; formal analysis, J.C.S., D.R.W., C.B., P.W., T.C.W., R.M., L.J., R.J.D. and J.E.C.; writing—original draft, review and editing, J.C.S., D.R.W., C.S.T. and J.R.; funding acquisition, C.S.T. and J.R.; resources, D.Y.L., J.C., C.S.T. and J.R.; supervision, C.S.T. and J.R.

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Correspondence to Jared Rutter.

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Integrated supplementary information

Supplementary Figure 1 Additional images of flow gating and IHC in mouse and human.

(a) Gating startegy for sorting of Lgr5-EGFP positive stem cells for transcript abundance. Top showing final gating for collection of GFP-low, GFP-mid, and GFP-high cells for transcript abundance. Bottom showing full gating strategy exclusion of cell debris and purification of singlet cells. (b) IHC of VDAC1 and MPC1 throughout the mouse small intestine from proximal to distal showing staining of crypt base and differentiating transient amplifying cells. (scale bar = 20 μm). (c) Human Protein Atlas (http://www.proteinatlas.org) images of duodenum, small intestine, and colon stained for TFAM, NRF1, PDK1, and CK20 (scale bar = 20 μm (b), 100 μm (c)).

Supplementary Figure 2 Drosophila MPC regulates stem cell proliferation.

(a) esg-GAL4 used to target RNAi as indicated or MPC overexpression (o/e) under infected conditions (scale bar = 50 μm). pHH3 + cells was quantified per intestine. (Control n = 10 (no infection) Control (with infection) n = 10, MPC O/E n = 10, LDH RNAi n = 10 MPC RNAi n = 10 PDH RNAi n = 10) (b) Western blot analysis to detect dMPC1 protein in control animals, dMPC1 mutants, HSP70-GAL4 controls, and HSP70 > UAS-dMPC1-dMPC2 transgenic animals following a 30-minute heat treatment and four hour recovery. Data are mean ± s.e.m. P < 0.05, P < 0.01, P < 0.001. All p values were calculated using Student’s t-test. Unprocessed western blots are provided in Supplementary Figure 7.

Supplementary Figure 3 MPC1 allele and additional quantification of in vivo phenotype.

(a) Schematic of MPC1 allele used for inducible knockout. (b) Close-up images of villi tip from MPC1 knockout stained for H&E, alcian blue, MPC1, VDAC and CK20 (scale bar = 20 μm). (c) Body weight for control and MPC1 knockout animals 30 days post-treatment. (n = 5 male control and knockout, n = 6 female control, = 3 knockout) (d) Total crypt + villi height and crypt height from individual regions of the small intestine. (n = 9 control, = 10 knockout for crypt + villi, n = 10 control, = 9 knockout for crypt height from each region) (e) Quantification of Alcian Blue positive cells per area of the proximal small intestine. (n = 10 control and knockout) (f) Quantification fo BrdU positive cells per crypt of proximal small intestine. (n = 9 control, = 10 knockout) (g) Images of Olfm4 and Lgr5 in situ in control and MPC1 knockout. (scale bar = 50μm) (h) Additional quantification of in situ staining. (n = 9 control, n = 10 knockout) (i) Quantification of Lrig1 IHC staining in control and MPC1 knockout proximal small intestine. (n = 9 control, n = 10 knockout) Data are mean ± s.e.m. P < 0.05, P < 0.01, P < 0.001. All p values were calculated using Student’s t-test.

Supplementary Figure 4 Additional characterization of in vito Mpc1 Lgr5-KO.

(a) Flow cytometry profile for organoids from control and MPC1 knockout cultures showing GFP positivity. (b) Long-term cultures retain increased growth ability throughout extended passaging (over 2 months) (n = 15 control and knockout, scale bar = 200 μm) (c) Control and MPC1 knockout organoid western blots for MPC1 and MPC2 and pyruvate dehydrogenase (phospho 293 and total). (d) Transcript abundance of MPC1 knockout organoids showing stem and differentiation marks (n = 3). (e) Quantification of specific Acetyl Histone H3 marks in control and knockout organoids (paired control set to 1.0) (n = 8 organoids). (f) Steady state metabolite abundance for control and MPC1 knockout organoids (n = 6 control and knockout). Data are mean ± s.e.m. P < 0.05, P < 0.01, P < 0.001. All p values were calculated using Student’s t-test. Unprocessed western blots are provided in Supplementary Figure 7.

Supplementary Figure 5 Effects of UK-5099 in maintaining organoids.

(a) Organoid formation from different regions of small intestine and colon with treatment conditions (n = 6 per condition, p values by t-test with respect to wENR for each location). (b) Loss of passaging efficiency in crypts maintained in wENR compared to UK-5099. When identical cell numbers are passaged normally, wENR treated are more likely to fail to passage. Images are of multiple matrigel/organoid spots of identical size (5uL) on a 6 well plate tiled to make one image (organoids from n = 3 wells were counted and number per well used for quantification, scale bar = 2000 μm). (c) Formation of hyperintense lumens in crypt organoids grown in wENR compared to UK-5099 3 days after changing media to remove CHIR99021 and Valproic acid (n = 69 total organoids from 6 individual wells). (d) Dose curves for individual drugs in supporting organoid formation from crypts (n = 8 wENR, all other conditions n = 6, p value by t-test with respect to wENR). Data are mean ± s.e.m. P < 0.05, P < 0.01, P < 0.001. All p values were calculated using Student’s t-test.

Supplementary Figure 6 Effects of UK-5099 and MPC over expression.

(a) Flux profiling of U-C13 Glucose incorporation into Citrate for tMEF and C2C12 cell lines treated with UK-5099 or Valproic Acid over 4 hours (n = 3 per condition per timepoint). (b) Representative images of infected Lgr5-EGFP (green) organoids with either Empty Vector-mCherry (in red) or MPC1-iRFP (in blue) and MPC2 mCherry (in red). Traces below represent intensity of each color over the length of the line outlined by white dotted line in the image. (n = 4 organoids with at least 15 infected cells per organoid counted). (c) ENCODE track for Myc and associated transcription factors localized to the Mpc1 promoter. (d) Model where crypt homeostasis involves low pyruvate oxidation at the base which increases during differentiation. MPC1 loss leads to reduced pyruvate oxidation, increased glycolysis, increased proliferation, and an expansion of the stem cell compartment within the crypt. Data are mean ± s.e.m. P < 0.05, P < 0.01, P < 0.001. All p values were calculated using Student’s t-test.

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Schell, J., Wisidagama, D., Bensard, C. et al. Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism. Nat Cell Biol 19, 1027–1036 (2017). https://doi.org/10.1038/ncb3593

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