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ResearchIn-Press PreviewPulmonologyStem cells Open Access | 10.1172/jci.insight.163820

Hypoxia enhances IPF mesenchymal progenitor cell fibrogenicity via the lactate/GPR81/HIF1α pathway

Libang Yang,1 Adam Gilbertsen,1 Hong Xia,1 Alexey Benyumov,1 Karen A. Smith,2 Jeremy A. Herrera,1 Emilian Racila,3 Peter B. Bitterman,1 and Craig A. Henke1

1Department of Medicine, University of Minnesota, Minneapolis, United States of America

2CSENG Biomedical Engineering, University of Minnesota, Minneapolis, United States of America

3Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, United States of America

Find articles by Yang, L. in: JCI | PubMed | Google Scholar

1Department of Medicine, University of Minnesota, Minneapolis, United States of America

2CSENG Biomedical Engineering, University of Minnesota, Minneapolis, United States of America

3Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, United States of America

Find articles by Gilbertsen, A. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Minnesota, Minneapolis, United States of America

2CSENG Biomedical Engineering, University of Minnesota, Minneapolis, United States of America

3Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, United States of America

Find articles by Xia, H. in: JCI | PubMed | Google Scholar

1Department of Medicine, University of Minnesota, Minneapolis, United States of America

2CSENG Biomedical Engineering, University of Minnesota, Minneapolis, United States of America

3Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, United States of America

Find articles by Benyumov, A. in: JCI | PubMed | Google Scholar

1Department of Medicine, University of Minnesota, Minneapolis, United States of America

2CSENG Biomedical Engineering, University of Minnesota, Minneapolis, United States of America

3Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, United States of America

Find articles by Smith, K. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Minnesota, Minneapolis, United States of America

2CSENG Biomedical Engineering, University of Minnesota, Minneapolis, United States of America

3Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, United States of America

Find articles by Herrera, J. in: JCI | PubMed | Google Scholar

1Department of Medicine, University of Minnesota, Minneapolis, United States of America

2CSENG Biomedical Engineering, University of Minnesota, Minneapolis, United States of America

3Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, United States of America

Find articles by Racila, E. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Minnesota, Minneapolis, United States of America

2CSENG Biomedical Engineering, University of Minnesota, Minneapolis, United States of America

3Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, United States of America

Find articles by Bitterman, P. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Minnesota, Minneapolis, United States of America

2CSENG Biomedical Engineering, University of Minnesota, Minneapolis, United States of America

3Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, United States of America

Find articles by Henke, C. in: JCI | PubMed | Google Scholar

Published January 19, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.163820.
Copyright © 2023, Yang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 19, 2023 - Version history
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Abstract

Hypoxia is a sentinel feature of IPF. The IPF microenvironment contains high lactate levels and hypoxia enhances cellular lactate production. Lactate, acting through the GPR81 lactate receptor, serves as a signal molecule regulating cellular processes. We previously identified intrinsically fibrogenic mesenchymal progenitor cells (MPCs) in the lungs of IPF patients that drive fibrosis. However, whether hypoxia enhances IPF MPC fibrogenicity is unclear. We hypothesized that hypoxia increases IPF MPC fibrogenicity via lactate and its cognate receptor GPR81. Here we show that hypoxia promotes IPF MPC self-renewal. The mechanism involves hypoxia-mediated enhancement of LDHA function and lactate production and release. Hypoxia also increases HIF1α levels, which in turn augments the expression of GPR81. Exogenous lactate operating through GPR81 promotes IPF MPC self-renewal. IHC analysis of IPF lung tissue demonstrate IPF MPCs expressing GPR81 and hypoxic markers on the periphery of the fibroblastic focus. We show that hypoxia enhances IPF MPC fibrogenicity in vivo. We demonstrate that knock-down of GPR81 inhibits hypoxia-induced IPF MPC self-renewal in vitro and attenuates hypoxia-induced IPF MPC fibrogenicity in vivo. Our data demonstrate that hypoxia creates a feed-forward loop that augments IPF MPC fibrogenicity via the lactate/GPR81/HIF1α pathway.

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Version history
  • Version 1 (January 19, 2023): In-Press Preview
  • Version 2 (February 22, 2023): Electronic publication
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