ABCB5+ mesenchymal stromal cells therapy protects from hypoxia by restoring Ca2+ homeostasis in vitro and in vivo

Stem Cell Research & Therapy

Research

Markus H. Frank¹  Kaixuan Yan²  Jiaxing Zheng²  Lin Li²  Michael Keese³  Prama Pallavi⁴  Richard Magdeburg⁵  Mark Andreas Kluth⁶  Christoph Ganss⁷  Benito Yard⁸ 

[1] Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA;Transplant Research Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA;Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA;School of Medical and Health Sciences, Edith Cowan University, Perth, WA, Australia;Department of Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany;European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany;Department of Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany;European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany;Department for General and Visceral Surgery, Theresienkrankenhaus Mannheim, Mannheim, Germany;Department of Surgery, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68161, Mannheim, Germany;Department of Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany;European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany;Department of Surgery, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68161, Mannheim, Germany;Department of Surgery, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68161, Mannheim, Germany;TICEBA GmbH, Heidelberg, Germany;TICEBA GmbH, Heidelberg, Germany;RHEACELL GmbH & Co. KG, Heidelberg, Germany;V Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany;

关键词: Peripheral artery disease;    Mesenchymal stromal cells;    Stem cell therapy;    Hypoxia;    Calcium ion;    Endothelial cells;    Angiogenesis;   

DOI  :  10.1186/s13287-022-03228-w

 received in 2022-03-14, accepted in 2022-12-21,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundHypoxia in ischemic disease impairs Ca2+ homeostasis and may promote angiogenesis. The therapeutic efficacy of mesenchymal stromal cells (MSCs) in peripheral arterial occlusive disease is well established, yet its influence on cellular Ca2+ homeostasis remains to be elucidated. We addressed the influence of ATP-binding cassette subfamily B member 5 positive mesenchymal stromal cells (ABCB5+ MSCs) on Ca2+ homeostasis in hypoxic human umbilical vein endothelial cells (HUVECs) in vitro and in vivo.MethodsHypoxia was induced in HUVECs by Cobalt (II) chloride (CoCl2) or Deferoxamine (DFO). Dynamic changes in the cytosolic- and endoplasmic reticulum (ER) Ca2+ and changes in reactive oxygen species were assessed by appropriate fluorescence-based sensors. Metabolic activity, cell migration, and tube formation were assessed by standard assays. Acute-on-chronic ischemia in Apolipoprotein E knock-out (ApoE−/−) mice was performed by double ligation of the right femoral artery (DFLA). ABCB5+ MSC cells were injected into the ischemic limb. Functional recovery after DFLA and histology of gastrocnemius and aorta were assessed.ResultsHypoxia-induced impairment of cytosolic and ER Ca2+ were restored by ABCB5+ MSCs or their conditioned medium. Similar was found for changes in intracellular ROS production, metabolic activity, migratory ability and tube formation. The restoration was paralleled by an increased expression of the Ca2+ transporter Sarco-/endoplasmic reticulum ATPase 2a (SERCA2a) and the phosphorylation of Phospholamban (PLN). In acute-on-chronic ischemia, ABCB5+ MSCs treated mice showed a higher microvascular density, increased SERCA2a expression and PLN phosphorylation relative to untreated controls.ConclusionsABCB5+ MSCs therapy can restore cellular Ca2+ homeostasis, which may beneficially affect the angiogenic function of endothelial cells under hypoxia in vitro and in vivo.

【 授权许可】

CC BY   
© The Author(s) 2023

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