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New Strategy for Enhanced Stem Cell-based Cardiac Repair

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Review of “Paracrine Engineering of Human Explant-Derived Cardiac Stem Cells to Over-Express Stromal-Cell Derived Factor 1α Enhances Myocardial Repair” from Stem Cells by Stuart P. Atkinson

The injection of cardiac-derived cells into the heart represents a promising cell treatment for heart failure. Phase I clinical trials suggest that this strategy is safe and may be effective, and low cell engraftment rates [1, 2] suggests that factors secreted from the cells, rather than the cells themselves, are the important reparative/regenerative elements.

With this in mind, the laboratory of Darryl R. Davis (University of Ottawa Heart Institute, Canada) aimed to produce primary cardiac explant-derived cells (EDCs) stably expressing the potent cardio-protective cytokine SDF1α (stromal-cell derived factor 1α). Their study in Stem Cells suggests that this new strategy leads to enhanced angiogenesis, cell migration, hematopoiesis, and stem cell mobilization/homing via a potentiated paracrine mechanism, and contributes to enhanced stem cell-based cardiac repair [3].

The authors chose SDF1α due to the early and sustained upregulation of its receptor, CXCR4, within the infarct and infarct border zone following myocardial infarction (MI) and the known role of SDF1α in cardioprotection from ischemic injury [4, 5]. SDF1α expressing EDCs (represent a mesenchymal population within cardiac stem cells) displayed a broadened overall paracrine signature and this stimulated blood vessel formation, recruitment of progenitor cells, and cardiogenic differentiation in vitro, while enhancing cardiac repair (See Figure - reduced scar formation and increased tissue viabilitywithout altering grafting following transplantation into mice 1 week after experimental infarction. 

Further in vivo analysis demonstrated that the concentration of SDF1α in the infarct and infarct border regions increased, apoptosis decreased, and the generation of new myocytes also increased. Additionally, transplantation of SDF1α EDCs increased bone marrow cell recruitment; although they found that native c-Kit+ cardiac cells contributed little to the regenerative performance of EDCs.

This study suggests that SDF1α overexpression does represent an interesting new strategy for enhanced stem cell-based cardiac repair through the potentiation of paracrine-mediated reparative/regenerative actions. The researchers hope to next investigate possible synergistic treatments to further improve repair and also to clarify the interactions between SDF1α and the injured heart.

Discussion Points

  • How is SDF1α functioning?
  • What other factors may further promote enhanced stem cell-based cardiac repair?
  • What other strategies can we use to enhance stem cell-based cardiac repair?

References

  1. Terrovitis J, Lautamäki R, Bonios M, et al. Noninvasive Quantification and Optimization of Acute Cell Retention by In Vivo Positron Emission Tomography After Intramyocardial Cardiac-Derived Stem Cell Delivery. Journal of the American College of Cardiology 2009;54:1619-1626.
  2. Bonios M, Chang CY, Terrovitis J, et al. Constitutive HIF-1α Expression Blunts the Beneficial Effects of Cardiosphere-Derived Cell Therapy in the Heart by Altering Paracrine Factor Balance. J Cardiovasc Transl Res 2011;4:363-372.
  3. Tilokee EL, Latham N, Jackson R, et al. Paracrine Engineering of Human Explant-Derived Cardiac Stem Cells to Over-Express Stromal-Cell Derived Factor 1alpha Enhances Myocardial Repair. Stem Cells 2016;34:1826-1835.
  4. Askari AT, Unzek S, Popovic ZB, et al. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 2003;362:697-703.
  5. Penn MS, Mendelsohn FO, Schaer GL, et al. An open-label dose escalation study to evaluate the safety of administration of nonviral stromal cell-derived factor-1 plasmid to treat symptomatic ischemic heart failure. Circ Res 2013;112:816-825.