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NT‐3 Treatment as a Novel Cell-free Therapeutic Approach for Myocardial Infarction-associated Injury

Review of "Neurotrophin‐3 contributes to benefits of human embryonic stem cell‐derived cardiovascular progenitor cells against reperfused myocardial infarction" from STEM CELLS Translational Medicine by Stuart P. Atkinson

Recent research from the laboratory of Huang‐Tian Yang (Chinese Academy of Sciences, Shanghai, China) established that the transplantation of human embryonic stem cell‐derived cardiovascular progenitor cells (CVPCs) [1] significantly reduced cardiomyocyte death, improved cardiac function, and limited scar size in murine [2] and non-human primate myocardial infarction models [3]. Furthermore, the team also highlighted the role of interleukin‐4 and interleukin‐13 secreted by CVPCs in the polarization of macrophages into a reparative phenotype in the infarcted mouse heart [2].

In their follow-up research published recently in STEM CELLS Translational Medicine [4], Bi et al. sought to explore the cardioreparative function of other CVPC-secreted proteins by focusing on Neurotrophin-3 (NT3), a nervous system growth factor expressed by cardiovascular cells [5, 6]. Excitingly, this new study's findings support NT‐3 treatment as a novel cell-free therapeutic approach for myocardial infarction-associated injury.

The authors first confirmed that CVPCs secreted elevated levels of NT‐3 and improved cardiac function and fibrotic scar formation concomitant with reduced cardiomyocyte death and increased angiogenesis after their implantation into the infarcted mouse heart at the beginning of reperfusion following an hour of ischemia. Further detailed analysis of the role of NT-3 revealed that an injection of human recombinant NT‐3 mimicked the effect of CVPCs, while an NT‐3 neutralizing antibody inhibited any cardioreparative effect of CVPCs. Interestingly, the study also discovered both the expression of NT‐3 by mouse adult cardiomyocytes (described for the first time) and an increase in NT-3 basal levels following myocardial infarction; additionally, the knockdown of endogenous NT‐3 worsened myocardial injury.

Finally, mechanistic studies provided evidence that both exogenous and endogenous NT‐3 inhibited the apoptosis of cardiomyocytes following myocardial infarction by activating the extracellular signal‐regulated kinase (ERK) to reduce the levels of Bim (Bcl-2-like protein 11), a critical mitochondrial apoptosis activator.

Overall, these fascinating findings provide robust evidence for the crucial role of the neurotrophin family in repairing the infarcted heart and provide a platform for developing a safe and efficient cell free-approach to the treatment of myocardial infarction-associated injuries.

For more on the crucial role of Neurotrophin-3 in the infarcted heart, stay tuned to the Stem Cells Portal!

References

  1. Cao N, Liang H, Huang J, et al., Highly efficient induction and long-term maintenance of multipotent cardiovascular progenitors from human pluripotent stem cells under defined conditions. Cell Research 2013;23:1119-1132.
  2. Wang J, Liu M, Wu Q, et al., Human Embryonic Stem Cell-Derived Cardiovascular Progenitors Repair Infarcted Hearts Through Modulation of Macrophages via Activation of Signal Transducer and Activator of Transcription 6. Antioxidants & Redox Signaling 2019;31:369-386.
  3. Zhu K, Wu Q, Ni C, et al., Lack of Remuscularization Following Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitor Cells in Infarcted Nonhuman Primates. Circulation Research 2018;122:958-969.
  4. Bi W, Wang J, Jiang Y, et al., Neurotrophin-3 contributes to benefits of human embryonic stem cell-derived cardiovascular progenitor cells against reperfused myocardial infarction. STEM CELLS Translational Medicine 2021;10:756-772.
  5. Caporali A and Emanueli C, Cardiovascular Actions of Neurotrophins. Physiological Reviews 2009;89:279-308.
  6. Kawaguchi-Manabe H, Ieda M, Kimura K, et al., A novel cardiac hypertrophic factor, neurotrophin-3, is paradoxically downregulated in cardiac hypertrophy. Life Sciences 2007;81:385-392.