Stem cell mechanisms during left ventricular remodeling post-myocardial infarction: Repair and regeneration

Table 1 Stem cells differentiated into cardiomyocytes

Cell type	Method of differentiation	Ref.
ESCs	EB-mediated differentiation	[17,18]
iPS	Transdifferentiation of iPS cell factor-based reprogrammed cardiac fibroblasts using EB-based method + transwell CM co-culture system	[19]
	Direct reprogramming of cardiac fibroblasts in vivo by local delivery of GMT	[21]
	Suspension EB-mediated differentiation of reprogrammed adult fibroblasts	[22,23]
Bone marrow MSC	In vitro differentiation induced by treatment with 5-azacytadine	[27,28]
	In vivo differentiation of stem cells transplanted and mobilized to damaged myocardium	[29]
	In vivo differentiation of stem cells engrafted into the myocardium	[30]
	Differentiation using a cardiomyogenic differentiation medium containing insulin, DMSO, and ascorbic acid	[31]
Adipose-derived MSC	Co-culture in direct contact with contracting cardiomyocytes	[37]
	DMSO at 0.1% for 48 h	[38]
Amniotic fluid SCs	In vivo differentiation of cells transplanted into myocardium	[33]
	In vitro differentiation through EB formation	[35]
Umbilical cord blood SCs	Co-culture with primary rat neonatal ventricular myocytes	[32]
	Co-culture with mouse neonatal cardiomyocytes	[34]
Wharton's Jelly MSCs	In vitro differentiation induced by treatment with 5-azacytadine or by culture in cardiomyocyte CM	[36]
CS	Co-culture with neonatal rat cardiomyocytes	[41]
CSP	Treatment with oxytocin or trichostatin A	[48]

ESC: Embryonic stem cell; EB: Embryoid body; iPS: Induced pluripotent stem cells; SCs: Stem cells; CM: Conditioned medium; GMT: Gata4, Mef2c, and Tbx5; MSC: Mesenchymal stem cell; DMSO: Dimethylsulfoxide; CS: Cardiospheres; CSP: Cardiac side population.

Table 2 Stem cell trophic factors

Factor	Outcome	Ref.
↑Akt	Reduction cardiomyocyte loss	[52]
↓ NF-κβ	Anti-apoptotic effects	[53-55]
↓ TNF-α	Anti-apoptotic effects	[53-55]
↓ IL-6	Anti-apoptotic effects	[53-55]
↑ IL-10	Anti-apoptotic effects	[53-55]
↑ IL-6	Prevention activated neutrophil apoptosis via Stat3; regulation of neutrophil activation	[56-60]
↑ IL-10, ↑TNF-α, and ↑ IL-6	Macrophage M2 polarization	[53,61-65]
↓ Collagen I and III, ↓ TIMP-1 and ↓TGF-β	Reduction in fibrosis and scar size	[55,69-76]
↑ VEGF	Promote angiogenesis; improved contractile function	[77-86]
↑ IL-6	DC maturation inhibition	[60,66-68]
↑ IDO and ↑PGE2	Reduced T cell activation	[60,66-68]
↑ IDO and ↑PGE2	Decreased NK proliferation	[60]
Factor to be identified	B-Cell arrest	[60]

Akt: Serine/threonine kinase; NF-κβ: Nuclear factor κβ; TNF-α: Tumor necrosis factor α; IL-6: Interleukin 6; IL-10: Interleukin 10; TIMP-1: Tissue inhibitor of metalloproteinase 1; TGF-β: Transforming growth factor β; VEGF: Vascular endothelial growth factor; IDO: Indoleamine 2,3-dioxygenase; DC: Dendritic cell; NK: Natural killer cell; PGE2: Prostaglandin E2.

Table 3 Recently published clinical trials of stem cell therapies for acute treatment post-myocardial infarction

	Clinical trial	Outcome	Ref.
2010	Influence of bone marrow stem cells on left ventricular perfusion and ejection fraction in patients with acute myocardial infarction of anterior wall: Randomized clinical trial	Slight improvement of myocardial profusion	[109]
2011	HEBE trial	No significant improvement on regional or global function	[110]
2011	Late TIME trial	No improvement on global or regional function at 6 mo	[111]
2012	Stem cell treatment for acute myocardial infarction	Reduced LVESV, LVEDV, and infarct size	[109]
2012	CADUCEUS trial	Reduced scar mass, increased myocardium viability, regional contractility and wall thickness	[112]
2012	Enhanced mobilization of the bone marrow-derived circulating progenitor cells by intracoronary freshly isolated bone marrow cells transplantation in patients with acute myocardial infarction	Feasibility, safety, and improvement on recovery of LV contractility	[113]
2013	The C-CURE trial	Feasibility, safety and improved LV ejection fraction	[114]

LV: Left ventricular; LVESV: Left ventricular end systolic volume; LVEDV: Left ventricular end diastolic volumes; CADUCEUS: CArdiosphere-derived autologous stem cells to reverse ventricular dysfunction; C-Cure: Cardiopoietic stem cell therapy in heart failure.