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Identifying Stem Cell Factors which Repair the Heart

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Review of “Conditioned Medium from Human Amniotic Mesenchymal Stromal Cells Limits Infarct Size and Enhances Angiogenesis” from Stem Cells TM by Stuart P. Atkinson.

Animal models of myocardial infarction (MI) have suggested that adult bone marrow-derived mesenchymal stromal cells (BM-MSCs) can repair post-ischemic myocardial damage to a certain degree [1]. This is almost certainly mediated through the action of soluble paracrine factors [2], suggesting that if we can elucidate the factors involved we may able to assemble a defined cell-free soluble factor-based strategy. To this end, researchers from the group of Massimiliano Gnecchi have used conditioned medium (CM) from multipotent MSCs isolated from the amniotic membrane of human placenta (hAMCs) [3] to discover putative active soluble factors mediating cardiac protection and neovascularization [4].

The study first demonstrated that hAMC-CM protected against a loss in cell viability after MI-associated hypoxia/re-oxygenation (H/R) injury in rat cardiomyoblasts in vitro, reducing the apoptotic nuclear fragmentation and inhibiting caspase-3 cleavage, as compared to a fibroblast CM control. This coincided with the inhibition of proapoptotic pathways (SAPK/JNK and p38 MAPK), ERK1/2-MAPK signaling activation, and the upregulation of several anti-apoptotic genes (BCL2 and STAT3) and downregulation of proapoptotic factors (BAK1, TNF-, and FasL). hAMC-CM also promoted angiogenesis through the promotion of endothelial progenitor cells (EPCs) migration/motility and increased capillary formation by EPCs. Moving in vivo, intramyocardial injection of CM using a well-established model of MI-associated ischemia/reperfusion (I/R) injury in rats reduced the infarct zone and greatly reduced the number of apoptotic cells, as compared to saline and fibroblast CM controls. Analysis after 1 month also found that hAMC-CM prevented left ventricular wall thinning (See attached figure), reduced the scar area, and induced significant amounts of neoangiogenesis.

To find the factors residing in hAMC-CM that mediate the above effects, the researchers assessed both gene expression profiles and cytokine arrays. Comparing hAMCs and fibroblasts found 647 genes significantly upregulated in hAMC and 131 of these by more than twofold. These included genes associated with the extracellular region, extracellular matrix, and collagen, and of the 32 genes associated with the extracellular region, the researchers noted MDK and SPARC as putative paracrine cardio-protective mediators [5, 6]. The cytokine array highlighted several pro-angiogenic factors overexpressed by hAMCs, including PDGF-BB, bFGF, IGF-1, thrombopoietin, VEGF, and VEGF-D.

The discovery of hAMC-CM-derived factors which may mediate cardiac repair after MI could lead to the generation of a powerful cell-free therapeutic tool to promote cardioprotection and neoangiogenesis. This would provide a safe, efficient, and hopefully, effective treatment which may promote both quality of life and lifespan extension following such a major heart trauma. The authors do however note that the full exploration of the factors and indeed complex combinations of factors which provide the therapeutic effects of hAMC-CM will require both proteomic and functional approaches. Furthermore, they highlight a potential role of exosomes, previously suggested to play a role in cardio-protection mediated by MSC-based therapies [7], although exosome currently still remain the focus of intense research to full elucidate their mechanisms of action.

References

  1. Anversa P, Kajstura J, Rota M, et al. Regenerating new heart with stem cells. The Journal of clinical investigation 2013;123:62-70.
  2. Gnecchi M, Zhang Z, Ni A, et al. Paracrine mechanisms in adult stem cell signaling and therapy. Circulation research 2008;103:1204-1219.
  3. In 't Anker PS, Scherjon SA, Kleijburg-van der Keur C, et al. Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells 2004;22:1338-1345.
  4. Danieli P, Malpasso G, Ciuffreda MC, et al. Conditioned Medium From Human Amniotic Mesenchymal Stromal Cells Limits Infarct Size and Enhances Angiogenesis. Stem Cells Translational Medicine 2015;
  5. Sumida A, Horiba M, Ishiguro H, et al. Midkine gene transfer after myocardial infarction in rats prevents remodelling and ameliorates cardiac dysfunction. Cardiovascular research 2010;86:113-121.
  6. McCurdy S, Baicu CF, Heymans S, et al. Cardiac extracellular matrix remodeling: fibrillar collagens and Secreted Protein Acidic and Rich in Cysteine (SPARC). Journal of molecular and cellular cardiology 2010;48:544-549.
  7. Lai RC, Arslan F, Lee MM, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem cell research 2010;4:214-222.