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Loss of Epithelial Hypoxia-Inducible Factor Prolyl Hydroxylase 2 Accelerates Skin Wound Healing in Mice

Joanna Kaluckaa Emmy Noether Research Group, University of Technology, Dresden, Germany;b Institute of Pathology, University of Technology, Dresden, Germany;c Department of Nephrology and Hypertension, University Clinic, University of Erlangen-Nuremberg, Erlangen-Nuremberg, Germany

Andreas Ettingerd Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

Kristin Frankea Emmy Noether Research Group, University of Technology, Dresden, Germany;b Institute of Pathology, University of Technology, Dresden, Germany

Soulafa Mamlouka Emmy Noether Research Group, University of Technology, Dresden, Germany;b Institute of Pathology, University of Technology, Dresden, Germany

Rashim Pal Singha Emmy Noether Research Group, University of Technology, Dresden, Germany;b Institute of Pathology, University of Technology, Dresden, Germany

Katja Farhate Department of Cardiovascular Physiology, Universitätsmedizin Göttingen, Georg-August University, Göttingen, Germany

Antje Muschtera Emmy Noether Research Group, University of Technology, Dresden, Germany;b Institute of Pathology, University of Technology, Dresden, Germany

Susanne Olbrichc Department of Nephrology and Hypertension, University Clinic, University of Erlangen-Nuremberg, Erlangen-Nuremberg, Germany

Georg Breierb Institute of Pathology, University of Technology, Dresden, Germany;f DFG Research Center and Cluster of Excellence for Regenerative Therapies Dresden, University of Technology, Dresden, Germany

Dörthe M. Katschinskie Department of Cardiovascular Physiology, Universitätsmedizin Göttingen, Georg-August University, Göttingen, Germany

Wieland Huttnerd Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

Alexander Weidemannc Department of Nephrology and Hypertension, University Clinic, University of Erlangen-Nuremberg, Erlangen-Nuremberg, Germany

Ben Wielockxa Emmy Noether Research Group, University of Technology, Dresden, Germany;b Institute of Pathology, University of Technology, Dresden, Germany;f DFG Research Center and Cluster of Excellence for Regenerative Therapies Dresden, University of Technology, Dresden, GermanyCorrespondence[email protected]

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Abstract

Skin wound healing in mammals is a complex, multicellular process that depends on the precise supply of oxygen. Hypoxia-inducible factor (HIF) prolyl hydroxylase 2 (PHD2) serves as a crucial oxygen sensor and may therefore play an important role during reepithelialization. Hence, this study was aimed at understanding the role of PHD2 in cutaneous wound healing using different lines of conditionally deficient mice specifically lacking PHD2 in inflammatory, vascular, or epidermal cells. Interestingly, PHD2 deficiency only in keratinocytes and not in myeloid or endothelial cells was found to lead to faster wound closure, which involved enhanced migration of the hyperproliferating epithelium. We demonstrate that this effect relies on the unique expression of β₃-integrin in the keratinocytes around the tip of the migrating tongue in an HIF1α-dependent manner. Furthermore, we show enhanced proliferation of these cells in the stratum basale, which is directly related to their attenuated transforming growth factor β signaling. Thus, loss of the central oxygen sensor PHD2 in keratinocytes stimulates wound closure by prompting skin epithelial cells to migrate and proliferate. Inhibition of PHD2 could therefore offer novel therapeutic opportunities for the local treatment of cutaneous wounds.

ACKNOWLEDGMENTS

J.K., K.F., S.M., R.P.S., and A.M. are supported by the Emmy Noether program (the Deutsche Forschungsgemeinschaft [DFG], Germany). B.W. is an Emmy Noether fellow. This work was supported by grants (to B.W.) from the MeDDrive-Programm (TU Dresden, Germany) and DFG, Germany (WI 3291/1-1 and SPP 1190, The Tumor-Vessel Interface). A.W. is supported by a grant from the DFG (WE4275/3-1).

We thank the team of Roland Jung for excellent technical support, Vineeth Surendranath for HRE mapping, and Johannes Schödel and Vasuprada Iyengar for helpful discussions.

The work was performed as a collaborative project within the COST Action TD0901 HypoxiaNet.

We declare that we have no conflicts of interest.

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Loss of Epithelial Hypoxia-Inducible Factor Prolyl Hydroxylase 2 Accelerates Skin Wound Healing in Mice

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Loss of Epithelial Hypoxia-Inducible Factor Prolyl Hydroxylase 2 Accelerates Skin Wound Healing in Mice

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