Apoptosis of mesenchymal stem cells induced by hydrogen peroxide concerns both endoplasmic reticulum stress and mitochondrial death pathway through regulation of caspases, p38 and JNK

Abstract

Poor survival of mesenchymal stem cells (MSCs) compromised the efficacy of stem cell therapy for myocardial infarction. The increase of exogenous reactive oxygen species (ROS) in infracted heart is one of the important factors that challenged the survival of donor MSCs. In the study we aimed to evaluate the effect of oxidative stress on the cell death of MSCs and investigate its mechanisms in order to help with the identification of new biological compounds to reduce donor cells damage. Apoptosis of MSCs were evaluated with Hoechst 33342 staining and flow cytometry analysis. The mitochondrial membrane potential of MSCs was analyzed with JC-1 staining. Signaling pathways involved in H(2)O(2) induced apoptosis were analyzed with Western blot. H(2)O(2) induced apoptosis of MSCs in a dose- and time-dependent manner. H(2)O(2) induced apoptosis of MSCs via both endoplasmic reticulum (ER) and mitochondrial pathways rather than extrinsic apoptosis pathway. H(2)O(2) caused transient rather than sustained activation of p38 and JNK with no effect on ERK1/2 pathway. P38 was involved in the regulation of early apoptosis of MSCs while JNK was involved in the late apoptosis. P38 directed both ER stress and mitochondria death pathway in the early apoptosis. In conclusion, exogenous ROS was a major factor to induce apoptosis of MSCs. Both ER stress and mitochondria death pathway were involved in the apoptosis of MSCs. H(2)O(2) activated p38 that directed the above two pathways in the regulation of early apoptosis of MSCs while JNK was involved in the late apoptosis of MSCs.

Activation of Liver X Receptor Improves Viability of Adipose-Derived Mesenchymal Stem Cells to Attenuate Myocardial Ischemia Injury Through TLR4/NF-κB and Keap-1/Nrf-2 Signaling Pathways

“…Previous research has demonstrated that reactive oxygen species (ROS) generated in infarcted myocardium stimulates cardiomyocyte apoptosis (21) and decreases AD-MSCs survival after engraftment (38). Therefore, ROS generation was assessed in our experimental model using dihydroethidium (DHE) fluorescence.…”

Renovascular Hypertension Leads to DNA Damage and Apoptosis in Bone Marrow Cells

“…Oxidative stress has been shown to be one of the key proapoptotic factors since it directly damages cell membranes, proteins, and DNA; thereby, promoting cell senescence, comprising cell function and threatening cell survival (Wei et al, 2010;Zanichelli et al, 2012). ROS are involved in many of the physiological and pathological processes observed in hypertension, since it is capable of inducing oxidation and damage of macromolecules contributing to cellular damage and, consequently, cell death through apoptosis (Lavi et al, 2010;Endtmann et al, 2011;Worou et al, 2011).…”

“…MAPK (Wei et al, 2010). In addition, several in vitro studies suggest that Ang II-induced activation of NADPH oxidase results in upregulation of p38 MAPK (Lal et al, 1999;Chan et al, 2005).…”

Superoxide Flashes

“…As compared with selenite causing similar level of cell death, the H 2 O 2 treatment (120 M) elicited relatively mild increase of superoxide flash activity (1.6-fold elevation at 6 h). This perhaps reflects the fact that, in addition to the intrinsic mitochondrial pathway, H 2 O 2 -induced cell death is also mediated by extrinsic pathways, including cell death receptors signaling (25), endoplasmic reticulum stress (26), and direct activation of Bax (17).…”