Human cardiac progenitor cell activation and regeneration mechanisms: exploring a novel myocardial ischemia/reperfusion in vitro model

Maria J. Sebastiao, Margarida Serra, Rute Pereira, Itziar Palacios, Patricia Gomes-Alves, Paula M. Alves

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Abstract

Background: Numerous studies from different labs around the world report human cardiac progenitor cells (hCPCs) as having a role in myocardial repair upon ischemia/reperfusion (I/R) injury, mainly through auto/paracrine signaling. Even though these cell populations are already being investigated in cell transplantation-based clinical trials, the mechanisms underlying their response are still poorly understood. Methods: To further investigate hCPC regenerative process, we established the first in vitro human heterotypic model of myocardial I/R injury using hCPCs and human-induced pluripotent cell-derived cardiomyocytes (hiPSC-CMs). The co-culture model was established using transwell inserts and evaluated in both ischemia and reperfusion phases regarding secretion of key cytokines, hiPSC-CM viability, and hCPC proliferation. hCPC proteome in response to I/R was further characterized using advanced liquid chromatography mass spectrometry tools. Results: This model recapitulates hallmarks of I/R, namely hiPSC-CM death upon insult, protective effect of hCPCs on hiPSC-CM viability (37.6% higher vs hiPSC-CM mono-culture), and hCPC proliferation (approximately threefold increase vs hCPCs mono-culture), emphasizing the importance of paracrine communication between these two populations. In particular, in co-culture supernatant upon injury, we report higher angiogenic functionality as well as a significant increase in the CXCL6 secretion rate, suggesting an important role of this chemokine in myocardial regeneration. hCPC whole proteome analysis allowed us to propose new pathways in the hCPC-mediated regenerative process, including cell cycle regulation, proliferation through EGF signaling, and reactive oxygen species detoxification. Conclusion: This work contributes with new insights into hCPC biology in response to I/R, and the model established constitutes an important tool to study the molecular mechanisms involved in the myocardial regenerative process.

Original languageEnglish
JournalSTEM CELL RESEARCH THERAPY
Volume10
DOIs
Publication statusPublished - 7 Mar 2019

Keywords

  • Cardiac progenitor cells
  • myocardial infarction
  • Myocardial ischemia reperfusion injury
  • Proteomics
  • Ischemia-reperfusion injury

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