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Extracellular Vesicles: The Driving Force Behind Cardiac Progenitor Cell Therapy

Review of “Extracellular Vesicles Released by Allogeneic Human Cardiac Stem/Progenitor Cells as Part of Their Therapeutic Benefit” from STEM CELLS Translational Medicine by Stuart P. Atkinson

Researchers led by Reem Al‐Daccak (Université Paris‐Diderot, Hôpital Saint‐Louis, Paris, France) previously demonstrated that the potent immunomodulatory capacity of human cardiac progenitor cells (hCPCs) contributed towards cardiac repair after myocardial infarction [1-4], and their research prompted a successful multicenter phase I/II clinical trial of allogeneic hCPCs in human myocardial infarction patients [5]. The team now returns with a STEM CELLS Translational Medicine study using a tailored allogeneic in vitro human assay that mimics the clinical setting to demonstrate hCPC-derived extracellular vesicles as the driving force behind the regenerative response in the heart  [6].

Do extracellular vesicles represent the driving force behind hCPC therapy and a possible safe and effective cell-free treatment for myocardial infarction?

Hocine et al. employed HLA‐mismatched cells to analyze the effects of extracellular vesicles isolated from hCPC culture supernatant to provide for a more clinically relevant study. Interestingly, the authors discovered that the rapid uptake of extracellular vesicles by hCPCs led to the activation of MAPK/Erk pathway signaling, while extracellular vesicles released by allogeneic hCPCs had the ability to recruitment hCPCs to wound sites and enhance their proliferation through the activation of MAPK/Erk‐signalling. 

Furthermore, extracellular vesicles also profound affected cardiomyocytes, by promoting promote their survival and proliferation, and endothelial cells, by inducing their activity and promoting angiogenic processes via kinase phosphorylation and the activation of several downstream signaling pathways. Additionally, extracellular vesicles activated and enhanced the survival of recruited monocytes, but also polarized monocytes into an anti‐inflammatory pro‐angiogenic phenotype with the potential to promote neovascularization, healing, and repair in the injured heart.

Overall, this new study suggests that the transplantation of allogeneic hCPC-derived extracellular vesicles promotes a long-lasting pro-regenerative, pro-angiogenic, and anti-inflammatory state in the cells of the infarcted heart, thereby promoting functional recovery while avoiding problems related to transplanting stem cells.

For more on how extracellular vesicles represent the driving force behind the regenerative response following hCPC therapy for myocardial infarction, stay tuned to the Stem Cells Portal

References

  1. Lauden L, Boukouaci W, Borlado Luis R, et al., Allogenicity of Human Cardiac Stem/Progenitor Cells Orchestrated by Programmed Death Ligand 1. Circulation Research 2013;112:451-464.
  2. Boukouaci W, Lauden L, Siewiera J, et al., Natural killer cell crosstalk with allogeneic human cardiac-derived stem/progenitor cells controls persistence. Cardiovascular Research 2014;104:290-302.
  3. Hocine HR, Costa HE, Dam N, et al., Minimizing the risk of allo-sensitization to optimize the benefit of allogeneic cardiac-derived stem/progenitor cells. Scientific Reports 2017;7:41125.
  4. Dam N, Hocine HR, Palacios I, et al., Human Cardiac-Derived Stem/Progenitor Cells Fine-Tune Monocyte-Derived Descendants Activities toward Cardiac Repair. Frontiers in Immunology 2017;8.
  5. Fernández-Avilés F, Sanz-Ruiz R, Bogaert J, et al., Safety and Efficacy of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With ST-Segment Elevation Myocardial Infarction and Left Ventricular Dysfunction. Circulation Research 2018;123:579-589.
  6. Johnson MB, Niknam-Bienia S, Soundararajan V, et al., Mesenchymal Stromal Cells Isolated from Irradiated Human Skin Have Diminished Capacity for Proliferation, Differentiation, Colony Formation, and Paracrine Stimulation. STEM CELLS Translational Medicine 2019;8:925-934.