Introduction: Death of transplanted cells remains a major obstacle for cell therapy. CCAAT-enhancer-binding protein homologous protein (CHOP) is a multifunctional transcription factor that plays a key role in endoplasmic reticulum (ER) stress and cellular apoptosis.
Hypothesis: Transplantation of CHOP-deficient mesenchymal stem cells (MSCs) with reduced ER stress would enhance cardiac repair after a reperfused myocardial infarction (MI).
Methods: Bone marrow MSCs were isolated from male CHOP-/- mice (CHOP-MSCs) and their littermates (Wt-MSCs). Cultured MSCs were exposed to ER and oxidative stress. Wild-type (WT, C57BL/6) mice underwent a 30-min coronary occlusion followed by reperfusion, and 48 h later received intramyocardial injection of vehicle (n=16), Wt-MSCs (n=16), or CHOP-MSCs (n=17). Echocardiography was performed 4 d prior to coronary occlusion/reperfusion (BSL1) and at 48 h (BSL2) and 35 d after cell injection. Mice were sacrificed after 35 d.
Results: In vitro, CHOP-MSCs exhibited greater resistance to ER stress- and oxidative stress-induced apoptosis following exposure to Thapsigargin (TG) and hydrogen peroxide (H2O2), respectively, assessed by flow cytometry (Fig). In vivo, LV ejection fraction (EF) was significantly and similarly reduced in all groups at 48 h after MI (Fig). However, after 35 d, mice injected with CHOP-MSCs exhibited greater EF (Fig) and smaller LV end-diastolic volume compared with vehicle-treated mice. The improvements in cardiac parameters in CHOP-MSC group were significantly greater compared with Wt-MSCs, indicating that attenuated ER stress enhanced the benefits of MSC transplantation further.
Conclusions: We conclude that therapy with CHOP-deficient MSCs with reduced ER stress induces superior cardiac reparative benefits compared with WT MSCs. The use of CHOP-MSCs may potentially improve the outcomes of cell therapy for ischemic heart disease in humans.