Inhibition of Gap Junction Formation Prior to Implantation of Bone Marrow-Derived Mesenchymal Cells Improves Function in the Ischemic Myocardium

Santipongse Chatchavalvanich; Robert A Boomsma; Jack M Tietema; David L Geenen

doi:10.3390/ijms24119653

Inhibition of Gap Junction Formation Prior to Implantation of Bone Marrow-Derived Mesenchymal Cells Improves Function in the Ischemic Myocardium

Int J Mol Sci. 2023 Jun 2;24(11):9653. doi: 10.3390/ijms24119653.

Authors

Santipongse Chatchavalvanich¹, Robert A Boomsma², Jack M Tietema³, David L Geenen⁴

Affiliations

¹ Department of Basic Biomedical Sciences, Dr. William M. Scholl College of Podiatric Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
² Biology Department, Trinity Christian College, Palos Heights, IL 60463, USA.
³ Michigan State University College of Human Medicine, Grand Rapids, MI 49503, USA.
⁴ Physician Assistant Studies Department, College of Health Professions, Grand Valley State University, Grand Rapids, MI 49503, USA.

Abstract

Bone marrow-derived mesenchymal stem cells (BM-MSC) are reported to induce beneficial effects in the heart following ischemia, but a loss of these cells within hours of implantation could significantly diminish their long-term effect. We hypothesized that early coupling between BM-MSC and ischemic cardiomyocytes through gap junctions (GJ) may play an important role in stem cell survival and retention in the acute phase of myocardial ischemia. To determine the effect of GJ inhibition on murine BM-MSC in vivo, we induced ischemia in mice using 90 min left anterior descending coronary artery (LAD) occlusion followed by BM-MSC implantation and reperfusion. The inhibition of GJ coupling prior to BM-MSC implantation led to early improvement in cardiac function compared to mice in which GJ coupling was not inhibited. Our results with in vitro studies also demonstrated increased survival in BM-MSCs subjected to hypoxia after inhibition of GJ. While functional GJ are critical for the long-term integration of stem cells within the myocardium, early GJ communication may represent a novel paradigm whereby ischemic cardiomyocytes induce a "bystander effect" when coupled to newly transplanted BM-MSC and thus impair cell retention and survival.

Keywords: connexin; gap junction; ischemic myocardium; stem cell.

MeSH terms

Animals
Bone Marrow
Gap Junctions
Mesenchymal Stem Cell Transplantation* / methods
Mice
Myocardial Ischemia* / therapy
Myocardium
Myocytes, Cardiac

Grants and funding

This research was supported by Illinois Regenerative Medicine Institute (DLG), an American Heart Association Pre-doctoral Fellowship (SC) and by Grand Valley State University, Office of Undergraduate Research Student Summer Scholarship (JT, DLG). J.M.T. was also awarded the title of “Koeze Fellow” from the Mary Beth Koeze Endowed Fellowship as part of the Student Summer Scholarship Award.