Heat shock protein 60 regulates yolk sac erythropoiesis in mice

Cell Death Dis. 2019 Oct 10;10(10):766. doi: 10.1038/s41419-019-2014-2.

Abstract

The yolk sac is the first site of blood-cell production during embryonic development in both murine and human. Heat shock proteins (HSPs), including HSP70 and HSP27, have been shown to play regulatory roles during erythropoiesis. However, it remains unknown whether HSP60, a molecular chaperone that resides mainly in mitochondria, could also regulate early erythropoiesis. In this study, we used Tie2-Cre to deactivate the Hspd1 gene in both hematopoietic and vascular endothelial cells, and found that Tie2-Cre+Hspd1f/f (HSP60CKO) mice were embryonic lethal between the embryonic day 10.5 (E10.5) and E11.5, exhibiting growth retardation, anemia, and vascular defects. Of these, anemia was observed first, independently of vascular and growth phenotypes. Reduced numbers of erythrocytes, as well as an increase in cell apoptosis, were found in the HSP60CKO yolk sac as early as E9.0, indicating that deletion of HSP60 led to abnormality in yolk sac erythropoiesis. Deletion of HSP60 was also able to reduce mitochondrial membrane potential and the expression of the voltage-dependent anion channel (VDAC) in yolk sac erythrocytes. Furthermore, cyclosporine A (CsA), which is a well-recognized modulator in regulating the opening of the mitochondrial permeability transition pore (mPTP) by interacting with Cyclophilin D (CypD), could significantly decrease cell apoptosis and partially restore VDAC expression in mutant yolk sac erythrocytes. Taken together, we demonstrated an essential role of HSP60 in regulating yolk sac cell survival partially via a mPTP-dependent mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia / genetics
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Chaperonin 60 / genetics
  • Chaperonin 60 / metabolism*
  • Cyclosporine / pharmacology
  • Embryo, Mammalian / metabolism
  • Embryo, Mammalian / physiopathology
  • Embryonic Development / genetics*
  • Endothelial Cells / metabolism
  • Erythrocytes / metabolism
  • Erythropoiesis / genetics*
  • Erythropoiesis / physiology
  • Female
  • Gene Expression Regulation, Developmental / genetics
  • Hematopoietic Stem Cells / metabolism
  • Membrane Potential, Mitochondrial / drug effects
  • Membrane Potential, Mitochondrial / genetics
  • Mice
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Pregnancy
  • Voltage-Dependent Anion Channels / drug effects
  • Voltage-Dependent Anion Channels / metabolism
  • Yolk Sac / cytology*
  • Yolk Sac / growth & development
  • Yolk Sac / metabolism
  • Yolk Sac / pathology

Substances

  • Chaperonin 60
  • Hspd1 protein, mouse
  • Mitochondrial Proteins
  • Voltage-Dependent Anion Channels
  • Cyclosporine