Evaluation of cell therapy benefits based on smart copolymers combined to recombinant proteins after myocardial infarction in adult rats

• Grant number: 17/07024-3
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): July 01, 2017
• Effective date (End): October 31, 2019
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal researcher: José Eduardo Krieger
• Grantee: Camila Zogbi Nogueira Perez
• Home Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated research grant: 13/17368-0 - Cardiovascular genomics: mechanisms & novel therapeutics - CVGen mech2ther, AP.TEM

Abstract

Cardiomyocytes replacement in postnatal life has been one of the great challenges in regenerative medicine. The concept that cardiomyocytes proliferate actively during development and exit cell cycle right after birth has been defied in neonatal mammals. Previously, our group has demonstrated that one-day-old rats display cardiomyocyte neoformation when submitted to apex resection. However, seven-days-old rats showed to lose this potential and the repair is basically performed through scar formation which leads to cardiac remodeling (1). First evidences showed that genes related to inflammatory response pathways were differently expressed between those groups and that macrophages anti-inflammatory conditioned media (M2) was capable of recapitulating regenerative effects on neonatal cardiomyocytes in culture, rising proliferative index under stress conditions and preventing cardiac fibroblasts induced-differentiation through low collagen and ±SMA expression. Within targets, four cytokines (IL-4, IL-1², IL-6 and Fractalkine) were exclusively expressed in M2 conditioned media and considered candidates to these regenerative effects. Considering the importance of tissue engineering on regeneration/repair to damaged organs and tissues like myocardial infarction, and the challenges in finding efficient supplies which reduce tissue rejection, the aims of this work is to develop smart injectable thermosensitive copolymers combined to recombinant proteins in order to improve cardiac repair by managing inflammatory response right after injury in adults. In this context, smart copolymers will be developed based on fusion proteins such as ELP (elastin-like peptides) fused to candidate proteins, which could be tested separately or combined in different proportions. The pioneer spirit of manufacturing thermosensitive injectable hydrogels as scaffolds combined with candidate sequences of interleukins and/or fractalkine is to serve as a matrix to maximize tissue repair and improve local efficiency of bioactive molecules availability, in order to suppress sustained acute inflammation right after injury and stimulate regenerative effects with slight long-term cardiac remodeling, besides holding the potential of cell carriers. Collectively, the goals of this work aim to raise efficiency of new and pioneering therapeutic approaches to tissue repair right after myocardial infarction, achieving a better prognosis in long-term.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ZOGBI, CAMILA; OLIVEIRA, NATHALIA C.; LEVY, DEBORA; BYDLOWSKI, SERGIO P.; BASSANEZE, VINICIUS; NERI, ELIDA A.; KRIEGER, JOSE E. Beneficial effects of IL-4 and IL-6 on rat neonatal target cardiac cells. SCIENTIFIC REPORTS, v. 10, n. 1 JUL 23 2020. Web of Science Citations: 0.