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Promoting Cardiac Regeneration with an Effective Cell-Free Strategy

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Review of “Exosomes Derived From Akt-Modified Human Umbilical Cord Mesenchymal Stem Cells Improve Cardiac Regeneration and Promote Angiogenesis via Activating Platelet-Derived Growth Factor D” from Stem Cells Translational Medicine by Stuart P. Atkinson

Stem cell-derived vesicles known as exosomes may be very small (30 and 100 nm), but their application in a wide range of regenerative strategies has a very large potential! Exosomes come jam-packed with factors known to boost regeneration and repair of various tissues and have several advantages over the application of stem cells themselves. Such advantages include the ease of long-term storage, easy administration and cell internalization, and low immunogenicity.

These advantages led researchers from the laboratory of Wei Zhu (Jiangsu University, Zhenjiang, PR China) to assess the ability of exosomes derived from modified mesenchymal stem cells (MSCs) to promote cardiac regeneration. Specifically, the lab employed human umbilical cord-derived MSCs [1] overexpressing the serine/threonine-specific protein kinase Akt [2] in the hope of synergizing their reported cardiac regeneration capacities. 

Their new findings, published in Stem Cells Translational Medicine, now suggest that this cell-free strategy may be an effective means to promote cardiac regeneration [3].

The study began with the assessment of various heart parameters via echocardiography following treatment of a rat acute myocardial infarction model. When compared to vehicle control and unmodified MSC-exosomes, Akt-modified MSC exosomes came out on top! However, the authors ruled out decreased myocardial apoptosis or increased myocardial proliferation and migration as reasons for the added cardiac regenerative effect of Akt overexpression. What they did discover was an increase in angiogenic potential, indicated by heightened endothelial cell proliferation, migration, tube-like structure formation in vitro, and blood vessel formation in vivo (See figure - blood vessel formation in chick allantoic membrane).

So just how does Akt boost angiogenic potential? To answer this nagging question, the study finally assessed levels of the various cytokines usually packaged into exosomes, finding increased levels of PDGFD platelet derived growth factor-D (PDGF-D) in Akt-modified MSC exosomes and in the myocardium of treated hearts. Interestingly, silencing of PDGF-D expression by siRNA reduced the ability of Akt-modified MSC exosomes to increase endothelial cell migration and vessel formation, overall suggestive of a key role for PDGF-D in cardiac regeneration.

Overall, Akt-modified MSC exosomes represents a safe and effective cell-free strategy for cardiac regeneration via the induction of angiogenesis and may provide a therapeutic means to treat myocardial problems in human patients. Such a therapy could involve synergism of a this pro-angiogenic strategy with a complementary cardiac muscle targeted strategy in order to synergize regenerative potentials.

Keep tuned to the Stem Cells Portal to see any new advances in this exciting area!

References

  1. Zhao Y, Sun X, Cao W, et al. Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Relieve Acute Myocardial Ischemic Injury. Stem Cells Int 2015;2015:761643.
  2. Rosenberg M, Lutz M, Kuhl C, et al. Coculture with hematopoietic stem cells protects cardiomyocytes against apoptosis via paracrine activation of AKT. J Transl Med 2012;10:115.
  3. Ma J, Zhao Y, Sun L, et al. Exosomes Derived from Akt-Modified Human Umbilical Cord Mesenchymal Stem Cells Improve Cardiac Regeneration and Promote Angiogenesis via Activating Platelet-Derived Growth Factor D. STEM CELLS Translational Medicine 2017;6:51-59.