Open AccessEmbryonic Stem Cell‐Derived Cardiomyogenesis: A Novel Role for Calreticulin as a Regulator
Author(s) -
Papp Sylvia,
Dziak Ewa,
Opas Michal
Publication year - 2009
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.85
Subject(s) - calreticulin , biology , endoplasmic reticulum , microbiology and biotechnology , actin
A role for calreticulin, an endoplasmic reticulum (ER)‐resident, Ca 2+ ‐binding chaperone, has recently emerged in the context of cardiomyogenesis. We previously proposed calreticulin to be a novel cardiac fetal gene, because calreticulin knockout causes embryonic lethality in mice as a result of cardiac defects, it is transiently activated during heart development, and heart‐targeted overexpression of constitutively active calcineurin in calreticulin‐null mice rescues the lethal phenotype. Calreticulin affects Ca 2+ homeostasis and expression of adhesion‐related genes. Using cardiomyocytes derived from both calreticulin‐null and wild‐type embryonic stem (ES) cells, we show here that cardiomyogenesis from calreticulin‐null ES cells is accelerated but deregulated, such that the myofibrils of calreticulin‐null cardiomyocytes become disorganized and disintegrate with time in culture. We have previously shown that the disorganization of the actin cytoskeleton in calreticulin‐null cells may be explained, at least in part, by the downregulation of adhesion proteins, implying that calreticulin ablation causes adhesion‐related defects. Here, upon examination of adhesion proteins, we found that vinculin is downregulated in calreticulin‐null cardiomyocytes. We also found c‐Src activity to be higher in calreticulin‐null cardiomyocytes than in wild‐type cardiomyocytes, and c‐Src activity is affected by both calreticulin and [Ca 2+ ]. Finally, we show that calreticulin and calsequestrin, the major Ca 2+ storage proteins of the ER and sarcoplasmic reticulum, respectively, exhibit alternate distributions. This suggests that calreticulin may have a housekeeping role to play in mature cardiomyocytes as well as during cardiomyogenesis. We propose here that calreticulin, an ER Ca 2+ storage protein, is a crucial regulator of cardiomyogenesis whose presence is required for controlled cardiomyocyte development from ES cells. STEM CELLS 2009;27:1507–1515