In Situ Maturated Early-Stage Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Improve Cardiac Function by Enhancing Segmental Contraction in Infarcted Rats

Author(s):Show less -

Biagi, Diogo ^[1] ; Fantozzi, Evelyn Thais ^[1] ; Campos-Oliveira, Julliana Carvalho ^[1] ; Naghetini, Marcus Vinicius ^[1] ; Ribeiro, Jr., Antonio Fernando ^[1] ; Rodrigues, Sirlene ^[1] ; Ogusuku, Isabella ^{[1, 2, 3]} ; Vanderlinde, Rubia ^[1] ; Christie, Michelle Lopes Araujo ^[4] ; Mello, Debora Bastos ^[4] ; de Carvalho, Antonio Carlos Campos ^[4] ; Valadares, Marcos ^[1] ; Cruvinel, Estela ^[1] ; Dariolli, Rafael ^{[5, 1]}

Affiliation

^[1] PluriCell Biotech, BR-05508000 Sao Paulo - Brazil

^[2] Ludwig Maximilians Univ Munchen, Gene Ctr, D-81377 Munich - Germany

^[3] Ludwig Maximilians Univ Munchen, Dept Biochem, D-81377 Munich - Germany

^[4] Univ Fed Rio de Janeiro, Carlos Chagas Filho Inst Biophys, BR-21941902 Rio De Janeiro - Brazil

^[5] Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, New York, NY 10029 - USA

• Document type: Journal article
• Source: JOURNAL OF PERSONALIZED MEDICINE; v. 11, n. 5 MAY 2021.
• Web of Science Citations: 0

Abstract

The scant ability of cardiomyocytes to proliferate makes heart regeneration one of the biggest challenges of science. Current therapies do not contemplate heart re-muscularization. In this scenario, stem cell-based approaches have been proposed to overcome this lack of regeneration. We hypothesize that early-stage hiPSC-derived cardiomyocytes (hiPSC-CMs) could enhance the cardiac function of rats after myocardial infarction (MI). Animals were subjected to the permanent occlusion of the left ventricle (LV) anterior descending coronary artery (LAD). Seven days after MI, early-stage hiPSC-CMs were injected intramyocardially. Rats were subjected to echocardiography pre-and post-treatment. Thirty days after the injections were administered, treated rats displayed 6.2% human cardiac grafts, which were characterized molecularly. Left ventricle ejection fraction (LVEF) was improved by 7.8% in cell-injected rats, while placebo controls showed an 18.2% deterioration. Additionally, cell-treated rats displayed a 92% and 56% increase in radial and circumferential strains, respectively. Human cardiac grafts maturate in situ, preserving proliferation with 10% Ki67 and 3% PHH3 positive nuclei. Grafts were perfused by host vasculature with no evidence for immune rejection nor ectopic tissue formations. Our findings support the use of early-stage hiPSC-CMs as an alternative therapy to treat MI. The next steps of preclinical development include efficacy studies in large animals on the path to clinical-grade regenerative therapy targeting human patients. (AU)

• FAPESP's process: 16/50082-1 - Development of human keratinocytes and dermo-epidermal equivalents from pluripotent stem cells
• Grantee: Estela Mitie Cruvinel
• Support Opportunities: Research Grants - Innovative Research in Small Business - PIPE
• FAPESP's process: 15/50224-8 - Characterization of induced pluripotent stem cell-derived cardiomyocytes and cellular assays standardization
• Grantee: Diogo Gonçalves Biagi dos Santos
• Support Opportunities: Research Grants - Innovative Research in Small Business - PIPE