Rejuvenation of Senescent Endothelial Progenitor Cells by Extracellular Vesicles Derived From Mesenchymal Stromal Cells

Liyong Wang; Jianqing Wei; Andrea Da Fonseca Ferreira; Huilan Wang; Lukun Zhang; Qianhuan Zhang; Michael A Bellio; Xian-Ming Chu; Aisha Khan; Dushyantha Jayaweera; Joshua M Hare; Chunming Dong

doi:10.1016/j.jacbts.2020.08.005

Rejuvenation of Senescent Endothelial Progenitor Cells by Extracellular Vesicles Derived From Mesenchymal Stromal Cells

JACC Basic Transl Sci. 2020 Oct 28;5(11):1127-1141. doi: 10.1016/j.jacbts.2020.08.005. eCollection 2020 Nov.

Authors

Liyong Wang^{1

2}, Jianqing Wei^{3

4}, Andrea Da Fonseca Ferreira³, Huilan Wang⁴, Lukun Zhang³, Qianhuan Zhang³, Michael A Bellio³, Xian-Ming Chu³, Aisha Khan³, Dushyantha Jayaweera⁴, Joshua M Hare^{3

4}, Chunming Dong^{3

4}

Affiliations

¹ John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA.
² Dr. John T. Macdonald Foundation, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA.
³ Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.
⁴ Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.

Abstract

Mesenchymal stromal cell (MSC) transplantation is a form of the stem-cell therapy that has shown beneficial effects for many diseases. The use of stem-cell therapy, including MSC transplantation, however, has limitations such as the tumorigenic potential of stem cells and the lack of efficacy of aged autologous cells. An ideal therapeutic approach would keep the beneficial effects of MSC transplantation while circumventing the limitations associated with the use of intact stem cells. This study provides proof-of-concept evidence that MSC-derived extracellular vesicles represent a promising platform to develop an acellular therapeutic approach that would just do that. Extracellular vesicles are membranous vesicles secreted by MSCs and contain bioactive molecules to mediate communication between different cells. Extracellular vesicles can be taken up by recipient cells, and once inside the recipient cells, the bioactive molecules are released to exert the beneficial effects on the recipient cells. This study, for the first time to our knowledge, shows that extracellular vesicles secreted by MSCs recapitulate the beneficial effects of MSCs on vascular repair and promote blood vessel regeneration after ischemic events. Furthermore, MSCs from aged donors can be engineered to produce extracellular vesicles with improved regenerative potential, comparable to MSCs from young donors, thus eliminating the need for allogenic young donors for elderly patients.

Keywords: BM, bone marrow; CVD, cardiovascular disease; EC, endothelial cell; EPC, endothelial progenitor cell; EV, extracellular vesicle; FBS, fetal bovine serum; MEM, minimum essential medium; MI, myocardial infarction; MSC, mesenchymal stromal cell; NTA, nanotracking analysis; PBS, phosphate-buffered saline; TEV, tailored extracellular vesicle; VEGF, vascular endothelial growth factor; acellular; angiogenesis; extracellular vesicles; lin− BMC, lineage negative bone marrow cell; miR, microRNA; qPCR, quantitative transcription polymerase chain reaction; regeneration; senescence.