Reply: Exosomes are Comparable to Source Adipose Stem Cells in Fat Graft Retention with Up-Regulating Early Inflammation and Angiogenesis
Bin Chen, Lifei Guo
Abstract
Sir: We would like to thank Drs. Filippo Boriani and Francesca Perut for their thoughtful letter on the subject of exosome and its potential biomedical applications.1 In our study, unlike a similar article2 cited in the letter, which reported proinflammatory and angiogenic effects of extracellular vesicles isolated from adipose-derived stem cells, we specifically compared the functions of adipose-derived stem cell–derived exosomes (a subpopulation of extracellular vesicles) to those of their source cells. Our findings demonstrated these exosomes were more than comparable to their source cells in their ability to increase graft volume retention through proinflammation and angiogenesis. Although increasing evidence suggests that extracellular vesicles such as exosomes are promising in clinical applications,3 we agree with the letter authors that more knowledge is necessary to translate extracellular vesicle basic research into regenerative medicine applications, as preparation and classification methods are still being debated and refined. Extracellular vesicles differ in size and biogenesis; in fact, they are a heterogeneous family that can be classified into different subpopulations, each of which may have different functions,4 and our understanding of their functions remains limited. Reassessment of extracellular vesicle composition and functional properties of each subpopulation is important for future application.5 Therefore, the more accurate the separation, the better it is to understand the nature of extracellular vesicles. In our current studies, we isolate exosomes (range, 50 to 200 nm) by a protocol using a sequential molecular weight cutoff of 100 kDa and a filter of 100 nm. A variety of techniques have been or are currently being developed to separate and purify extracellular vesicles from a conditioned medium or biological fluids.6 However, it is necessary to develop greater precision isolation and purification strategies of specific populations of extracellular vesicles for clinical applications. It is now widely accepted that extracellular vesicles interact with recipient cells by delivering bioactive lipids, nucleic acids (mRNAs and miRNAs), and proteins.7 Regarding the consideration of the potential application of mesenchymal stem cell–derived extracellular vesicles in regenerative medicine, increasing evidence demonstrates that they have exhilarative therapeutic benefits, which is equal to those effects of whole mesenchymal stem cell treatment.7 In our study, exosomes and their source adipose-derived stem cells were actually compared in a lipotransfer model, and the result showed a similar effect between them. As a candidate for cell-free therapy, although the duration of therapeutic effects may be shorter than their source stem cells, the advantages of extracellular vesicles in terms of safety, controllability, and availability are not hard to imagine. However, to realize its clinical applications, several serious issues regarding their production, dosing, and storage must be further explored. According to our practices in this field, we strongly believe that the status of mesenchymal stem cells greatly affects the yield and quality of extracellular vesicles by altering their cargo compositions. For example, exosomes derived from hypoxia-treated adipose-derived stem cells displayed better effects in promoting the survival of fat grafts.8 This may imply a possibility of customized production of extracellular vesicles for specific applications. In summary, the exploration of extracellular vesicle application is an ongoing process. Based on these meaningful studies, we are bound to further understand the nature of extracellular vesicles and get closer to their practical application in regenerative medicine. DISCLOSURE The authors have no financial interest to declare in relation to this communication.