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Extracellular vesicles for tissue regeneration

Updated: Feb 17, 2021

Extracellular vesicles (EVs) are nano-sized membrane vesicles composed of exomes, microvesicles, and other heterogeneous vesicles. EVs are generally divided into three categories: 1) exosomes emitted from intracellular endosomes; 2) microvesicles that bud directly from the plasma membrane; and 3) apoptotic bodies released during apoptosis. They have been increasingly recognized as vital mediators of information transfer between cells due to their intercellular communication roles. These small vesicles have been detected in almost every biological fluid such as blood, saliva, urine, amniotic fluid, and bronchoalveolar lavage fluid. The EVs also have a role in transporting proteins, drugs, and nucleic acids to target specific cells and increase therapeutic cargo stability, indicating significant potential for tissue regeneration [1,2, 3].

Figure 1: Biogenesis of extracellular vesicles [3].

Extracellular vesicles derived from diverse cell types play an essential role in the regeneration following different diseases [4]. After the isolation process, which usually include density gradient centrifugation/ultracentrifugation, chromatography, filtration, and immunoaffinity, EVs can be utilized in regenerative medicine through several methods, combined with hydrogels, or directly injected into the tissue or the circulation [1,5]. Although effective therapies haven’t been achieved yet, it is worth discussing promising results obtained in relevant researches with animal models [4]. It has been shown that EVs are associated with bone metabolism, bone healing, and present mineralization capacity. They also significantly enhance wound healing, collagen synthesis, and neoangiogenesis in wound sites [6,7]. The mechanisms of tissue recovery after EVs treatment have been attributed in part to the vesicles’ ability to modulate mechanisms involved in the angiogenesis, such as cell proliferation and migration [8].

A recent study used discarded human heart tissue to isolate human heart-derived extracellular vesicles (hH-EVs). The potential of hH-EVs to induce proliferation, adhesion, angiogenesis, and wound healing was investigated in vitro. hH-EVs could promote decellularized porcine heart valve leaflets’ recellularization, modulating cellular processes and acting as bioactive molecules in cell repopulation. This finding highlights the potential of these particles for tissue regeneration and scaffold recellularization. The observed increase in recellularization was probably due to increased cell interiorization rate into the leaflet scaffold [9].

Figure 2: Isolation of heart-derived extracellular vesicles. [9].

In another study, the role of EVs in liver regeneration was analyzed. The first evidence that they can promote liver regeneration was shown by injecting EVs derived from human liver stem cells (HLSCs), a mesenchymal stromal cell (MSC)-like population resident in human adult liver, in a model of 70% hepatectomy in rats. Extracellular vesicles accelerated liver functional and morphological recovery and induced in vitro proliferation and resistance to apoptosis in human and rat hepatocytes. These studies, among others from medical literature, demonstrate that EVs represent a potential approach to address tissue regeneration and should be exploited in regenerative medicine [10,11].


1. Taverna S, Pucci M, Alessandro R. Extracellular vesicles: small bricks for tissue repair/regeneration. Ann Transl Med. 2017;5(4):83.

2. Lamichhane TN, Sokic S, Schardt JS, Raiker RS, Lin JW, Jay SM. Emerging roles for extracellular vesicles in tissue engineering and regenerative medicine. Tissue Eng Part B Rev. 2015;21(1):45-54.

3. Riazifar M, Pone EJ, Lötvall J, Zhao W. Stem Cell Extracellular Vesicles: Extended Messages of Regeneration. Annu Rev Pharmacol Toxicol. 2017;57:125-154.

4. Fuster-Matanzo et al. Acellular approaches for regenerative medicine: on the verge of clinical trials with extracellular membrane vesicles?. Stem Cell Research & Therapy (2015) 6:227

5. Bruno S, Porta S, Bussolati B. Extracellular vesicles in renal tissue damage and regeneration. Eur J Pharmacol. 2016;790:83-91.

6. Rubiani, Oriana & Marconi, Guya & Piattelli, Adriano & Diomede, Francesca & Pizzicannella, Jacopo. (2019). Human Oral Stem Cells, Biomaterials and Extracellular Vesicles: A Promising Tool in Bone Tissue Repair. International Journal of Molecular Sciences. 201920. 4987.

7. Zhang J, Guan J, Niu X et al. Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. J Transl Med 2015;13:49

8. Bi Chen, Qing Li, Bizeng Zhao, Yang Wang. Stem Cell-Derived Extracellular Vesicles as a Novel Potential Therapeutic Tool for Tissue Repair. Stem Cells Translational Medicine 2017;6:1753–1758

9. Leitolis A, Suss PH, Roderjan JG, et al. Human Heart Explant-Derived Extracellular Vesicles: Characterization and Effects on the In Vitro Recellularization of Decellularized Heart Valves. Int J Mol Sci. 2019;20(6):1279.

10. Bruno S, Chiabotto G, Camussi G. Extracellular Vesicles: A Therapeutic Option for Liver Fibrosis. Int J Mol Sci. 2020;21(12):4255.

11. Herrera M.B., Fonsato V., Gatti S., Deregibus M.C., Sordi A., Cantarella D., Calogero R., Bussolati B., Tetta C., Camussi G. Human Liver Stem Cell-Derived Microvesicles Accelerate Hepatic Regeneration in Hepatectomized Rats. J. Cell. Mol. Med. 2010;14:1605–1618.

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