Umbilical cord mesenchymal stromal cells engraft and transdifferentiate into cardiomyocyte-like cells following acute myocardial ischemia⋆

Zeynep Yigman; Elif Derya Ozdemir; Nilufer N Turan; A Tulga Ulus; Alp Can

doi:10.1016/j.acthis.2020.151578

Umbilical cord mesenchymal stromal cells engraft and transdifferentiate into cardiomyocyte-like cells following acute myocardial ischemia⋆

Acta Histochem. 2020 Sep;122(6):151578. doi: 10.1016/j.acthis.2020.151578. Epub 2020 Jul 2.

Authors

Zeynep Yigman¹, Elif Derya Ozdemir², Nilufer N Turan³, A Tulga Ulus⁴, Alp Can⁵

Affiliations

¹ Gazi University Faculty of Medicine, Department of Histology and Embryology, Yenimahalle, Ankara, 06560, Turkey. Electronic address: zeynepyigman@gazi.edu.tr.
² Gazi University Faculty of Pharmacy, Department of Pharmacology, Yenimahalle, Ankara, 06560, Turkey. Electronic address: elif.derya.ozdemir@gmail.com.
³ Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Warren Alpert School of Brown University, Providence, RI, 02903, USA. Electronic address: nilufer_turan_durel@brown.edu.
⁴ Hacettepe University Faculty of Medicine, Department of Cardiovascular and Thoracic Surgery, Sihhiye, Ankara, 06100, Turkey. Electronic address: uluss@yahoo.com.
⁵ Ankara University School of Medicine, Department of Histology and Embryology, Laboratories for Stem Cells and Reproductive Medicine, Sihhiye, Ankara, 06100, Turkey. Electronic address: alpcan@medicine.ankara.edu.tr.

PMID: 32778240
DOI: 10.1016/j.acthis.2020.151578

Abstract

Objective: Human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) gained importance in acute/chronic ischemic cardiomyopathy because of their outstanding regenerative potential in various pathologic conditions. The present study was designed to determine to what extent hUC-MSCs contribute to myocardial regeneration in acute experimental myocardial infarction (MI) in rats.

Methods: Animals were assigned into two groups; the control group received intramyocardial PBS injections, while the hUC-MSC group received calcein-AM-labeled 8.8 × 10⁶/kg hUC-MSCs. Three weeks following the acute MI induction, rats were sacrificed after assessing the left ventricular (LV) function using echocardiography. For the assessment of infarct size, the triphenyl tetrazolium chloride (TTC) test was used in isolated hearts. Collagen-rich scar tissue was demonstrated using Masson's trichrome staining, followed by the detection of cardiac troponin I (cTnI), α-sarcomeric actin (α-SA), von Willebrand factor (vWF), CD68 and CD206 expressions in control and cell-injected sections.

Results: Echocardiography revealed a significant difference (P = 0.037) in the LV ejection fraction between groups. TTC assays demonstrated a significant difference (P = 0.006) between the groups regarding the ratio of the infarcted LV area. Calcein-AM-loaded cells were identified mostly in ischemic myocardium. Transplanted cells also expressed human-specific cTnI, providing concrete proof of transdifferentiation into cardiomyocytes, and α-SA. vWF⁺ cells verified the neovascularization in the ischemic myocardium. Finally, a slight shift from pro-inflammatory to anti-inflammatory macrophages (CD68⁺/CD206⁺) was noted in both groups.

Conclusions: We found that the intramyocardial transplanted hUC-MSCs engrafted and partially transdifferentiated into cardiomyocytes, reduced scar formation, and induced angiogenesis through the association of pro/anti-inflammatory macrophages.

Keywords: Cardiac regeneration; Cell therapy; Human umbilical cord-derived mesenchymal stromal cells; Myocardial ischemia; Rat.

MeSH terms

Animals
Cells, Cultured
Echocardiography
Female
Humans
Immunohistochemistry
Male
Mesenchymal Stem Cells / cytology*
Mesenchymal Stem Cells / metabolism
Myocardial Ischemia / metabolism*
Myocardial Ischemia / pathology*
Myocytes, Cardiac / cytology*
Myocytes, Cardiac / metabolism
Neovascularization, Physiologic / physiology
Pregnancy
Rats
Rats, Wistar
Umbilical Cord / cytology*