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Dana Trisha N.

Wahab

4-BIO8

Ischemic heart disease, a group of cardiovascular diseases that includes myocardial

infarction, is the leading cause of death worldwide. The most common cause of heart failure is

acute myocardial infarction (AMI). AMI leads to a series of cellular events: apoptosis, necrosis

and hypertrophy of myocytes; impaired neovascularization; intestinal fibrosis and inflammation;

reduced contractility; and pathological remodeling. Most therapeutic methods focus on reducing

early mortality by regulating hemodynamics, rather than tissue regeneration to facilitate cardiac

repair to avoid heart failure. Mesenchymal stem cells (MSCs) have provided considerable

promise in regenerative therapy. In preclinical studies using MSCs for AMI, improved cardiac

function was observed. However, in animal studies, administered MSCs showed low (~2%)

engraftment levels and limited capacity to transdifferentiate into cardiomyocytes after

transplantation. Therefore, it was unlikely that the observed improvement in cardiac function

resulted from the contribution of MSCs to replenish cardiomyocte populations, but is instead a

result of MSC-induced immunomodulatory and remodeling effects. Regulatory and trophic

factors secreted by MSCs are collectively known as the MSC secretome. A typical MSC

secretion profile consists of growth factors, cytokines, extracellular matrix proteases, hormones,

and lipid mediators. In human MSC analysis, 132 unique proteins were identified using Liquid

Chromatography with Tandem Mass Spectrometry Detection and 72 using antibody arrays.

While current techniques have been able to identify factors expressed at high levels, a complete

list of expressed secretome factors is yet to be generated. Recent studies have suggested potential

mechanisms on how exogenous-culture-expanded MSCs contribute to cardiovascular repair.

MSC transdifferentiation into contractile cardiomyocytes is inefficient and only occurs in the
presence of native cardiomyocytes. Strong evidence also suggests that rat-derived MSCs secrete

trophic factors that induce activation and proliferation of cardiac progenitor cells in vitro,

although these progenitor cells possess only a limited capacity to differentiate into fully mature

cardiomyocytes with an adult phenotype. The most plausible explanation for MSC-mediated

cardiovascular repair is an effect on the host cells and its microenvironment due to its secreted

growth factors, cytokines, and other signaling molecules. MSCs are sources of

immunomodulatory agents and trophic factors involved in repair and regenerative processes.

Cardiomyocyte survival and apoptosis prevention is induced through activation of PKC,

PI3K/Akt, NF-kB, and STAT3 signaling. In animal models, neovascularization is mediated by

MSCs through paracrine signaling and have antiapoptotic, anti-inflammatory, and antifibrotic

effects on cardiomyocytes and endothelial cells. Furthermore, MSCs exert immunomodulatory

effects by inducing neighboring cells to secrete cytokines useful in inhibiting excessive

inflammation and pathological remodeling. Transplanted MSCs are often short-lived, thus,

physiological, genetic, molecular, and pharmacological strategies are utilized to extend MSC

survival and improve response to highly dynamic signaling cues during myocardial infarction.

Available trial results are not as promising due to the use of nonoptimized MSC formulations and

poor understanding of how MSCs induce cardiovascular repair. Preconditioning MSCs to

improve homing, survival, and secretome control the is currently favored approach for regulating

cells. In addition, clarification of the underlying signaling pathways should develop more

effective preconditioning regiments to activate/inhibit relevant pathways to maximize therapeutic

effect.
Reference:

Ranganath, S., Levy, O., Inamdar, M., & Karp, J. (2012). Harnessing the Mesenchymal Stem

Cell Secretome for the Treatment of Cardiovascular Disease. Cell Stem Cell, 10(3), 244-258.

doi:10.1016/j.stem.2012.02.005