Effects of Heme Oxygenase-1 on c-Kit-Positive Cardiac Cells

Qianhong Li,Roberto Bolli,Chandrashekhar Dasari,Ding Li,Mohamed Riad Abdelgawad Abouzid,Ahmed Muaaz Umer,Asma Arshia,Yiru Guo

doi:10.3390/ijms222413448

Qianhong Li, Roberto Bolli + Show 6 more

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https://doi.org/10.3390/ijms222413448

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Abstract

Heme oxygenase-1 (HO-1) is one of the most powerful cytoprotective proteins known. The goal of this study was to explore the effects of HO-1 in c-kit-positive cardiac cells (CPCs). LinNEG/c-kitPOS CPCs were isolated and expanded from wild-type (WT), HO-1 transgenic (TG), or HO-1 knockout (KO) mouse hearts. Compared with WT CPCs, cell proliferation was significantly increased in HO-1TG CPCs and decreased in HO-1KO CPCs. HO-1TG CPCs also exhibited a marked increase in new DNA synthesis during the S-phase of cell division, not only under normoxia (21% O2) but after severe hypoxia (1% O2 for 16 h). These properties of HO-1TG CPCs were associated with nuclear translocation (and thus activation) of Nrf2, a key transcription factor that regulates antioxidant genes, and increased protein expression of Ec-SOD, the only extracellular antioxidant enzyme. These data demonstrate that HO-1 upregulates Ec-SOD in CPCs and suggest that this occurs via activation of Nrf2, which thus is potentially involved in the crosstalk between two antioxidants, HO-1 in cytoplasm and Ec-SOD in extracellular matrix. Overexpression of HO-1 in CPCs may improve the survival and reparative ability of CPCs after transplantation and thus may have potential clinical application to increase efficacy of cell therapy.

Highlights

The adult mammal heart contains a population of cells that express c-kit, the stem cell factor receptor, but lack hematopoietic lineage markers, referred to as linNEG/c-kitPOS cardiac cells (CPCs) [1,2,3,4]
Minced hearts isolated from WT, Heme oxygenases (HO)-1TG, and HO-1KO mice were cultured in 60 mm plates by the primary explant technique (Figure 1)
Elucidating the effects of Heme oxygenase-1 (HO-1) on CPC proliferation and DNA synthesis may enhance and facilitate the culture of CPCs in vitro and establish a new approach for potential clinical applications to increase the efficacy of cell therapy for heart failure in vivo

Summary

Introduction

The adult mammal heart contains a population of cells that express c-kit, the stem cell factor receptor, but lack hematopoietic lineage markers, referred to as linNEG/c-kitPOS cardiac cells (CPCs) [1,2,3,4]. Many preclinical studies have demonstrated that administration of CPCs to animals with ischemic heart failure can produce an improvement in left ventricular (LV) performance and remodeling [1,5,6,7,8,9,10,11,12,13,14,15,16,17] These results are encouraging, the therapeutic utility of CPCs is limited by the fact that the vast majority of transplanted CPCs die and/or fail to engraft shortly after their delivery into the damaged heart [1,9,10], so that, after 4–5 weeks,

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