Cell Therapy With Human ESC-Derived Cardiac Cells: Clinical Perspectives

Abstract

In the ongoing quest for the "ideal" cell type for heart repair, pluripotent stem cells (PSC) derived from either embryonic or reprogrammed somatic cells have emerged as attractive candidates because of their unique ability to give rise to lineage-specific cells and to transplant them at the desired stage of differentiation. The technical obstacles which have initially hindered their clinical use have now been largely overcome and several trials are under way which encompass several different diseases, including heart failure. So far, there have been no safety warning but it is still too early to draw definite conclusions regarding efficacy. In parallel, mechanistic studies suggest that the primary objective of "remuscularizing" the heart with PSC-derived cardiac cells can be challenged by their alternate use as ex vivo sources of a biologically active extracellular vesicle-enriched secretome equally able to improve heart function through harnessing endogenous repair pathways. The exclusive use of this secretome would combine the advantages of a large-scale production more akin to that of a biological medication, the likely avoidance of cell-associated immune and tumorigenicity risks and the possibility of intravenous infusions compatible with repeated dosing.

Engineering Extracellular Matrix Proteins to Enhance Cardiac Regeneration After Myocardial Infarction

“…In addition to providing novel engineering strategies for cardiac repair, more critical analysis of CM proliferation assays and induction of CM proliferation by microRNA, metabolic switch, or small molecule is necessary to inform the field to efficiently reach the goal of myocardial regeneration (Leone and Engel, 2019 ). A recent phase I clinical trial (ESCORT, NCT02057900) with fibrin and Matrigel composites incorporating human embryonic stem cell (hESC)-derived cardiac progenitor cells (Isl1 + ) proved the safety of the approach (Menasche et al, 2018 ; Menasché, 2020 ), which showed a synergistic contribution to the regeneration of the myocardium without apparent integration of the delivered cardiac cells. Thus, a protein engineering strategy could be a starting point to target a specific receptor and well-defined signal pathways (e.g., Hippo/Yap) (Bassat et al, 2017 ; Morikawa et al, 2017 ) ( Figure 1 ).…”

Mesenchymal and induced pluripotent stem cell–based therapeutics: a comparison

“…The forced expression of these factors returned the cells to an embryonic state, allowing them to once again differentiate into all germ layers (Takahashi et al 2007a ). In this manner, the ethical issues of using promising embryonic stem cell–derived therapeutic products (Menasché 2020 ) were circumvented, earning Shinya Yamanaka, the researcher who pioneered the method with murine cells in 2006 (Takahashi and Yamanaka 2006 ), the Nobel Prize in 2012 (The Nobel Prize 2022 ).…”

Extracellular vesicles secreted by human cardiosphere-derived cells attenuate electrophysiological remodelling in an in vitro model of atrial fibrillation

“…In 2021 there were only 22 clinical trials testing the beneficial effects of EVs, and none were in the cardiac field [202]. There is now one planned clinical trial with EVs from iPSCderived CPCs [203]. Main advantages of cellular and acellular products (which include EVs) are summarized in Figure 1.9.…”

“…ECM and cells isolated from different tissues present some common characteristics but also some differences that need to be controlled and taken into account when extrapolating the results [255,[259][260][261][262][263]. In general, using the same tissue source as the intended target has proven superior efficacy [203,205,264]. Even inside the same tissue, there may be similar but different cell types, and these slight differences may significantly influence the therapeutic properties [132].…”