Induced Pluripotent Stem Cell‐Derived Extracellular Vesicles Promote Wound Repair in a Diabetic Mouse Model via an Anti‐Inflammatory Immunomodulatory Mechanism

Abstract

Extracellular vesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) have recently been explored in clinical trials for treatment of diseases with complex pathophysiologies. However, production of MSC EVs is currently hampered by donor‐specific characteristics and limited ex vivo expansion capabilities before decreased potency, thus restricting their potential as a scalable and reproducible therapeutic. Induced pluripotent stem cells (iPSCs) represent a self‐renewing source for obtaining differentiated iPSC‐derived MSCs (iMSCs), circumventing both scalability and donor variability concerns for therapeutic EV production. Thus, it is initially sought to evaluate the therapeutic potential of iMSC EVs. Interestingly, while utilizing undifferentiated iPSC EVs as a control, it is found that their vascularization bioactivity is similar and their anti‐inflammatory bioactivity is superior to donor‐matched iMSC EVs in cell‐based assays. To supplement this initial in vitro bioactivity screen, a diabetic wound healing mouse model where both the pro‐vascularization and anti‐inflammatory activity of these EVs would be beneficial is employed. In this in vivo model, iPSC EVs more effectively mediate inflammation resolution within the wound bed. Combined with the lack of additional differentiation steps required for iMSC generation, these results support the use of undifferentiated iPSCs as a source for therapeutic EV production with respect to both scalability and efficacy.

Microenvironment Remodeling Self-Healing Hydrogel for Promoting Flap Survival

“…Treatment of HUVECs with different concentrations of EVs exerted significant effects on the cells, including the promotion of cell migration and tube formation in a dose-dependent manner (Figs. S6 and S7 ), consistent with previous reports on the strong biological activity of EVs [ 30 , 31 ].…”

Stem Cell-Derived Extracellular Vesicles: Promising Therapeutic Opportunities for Diabetic Wound Healing

“…In addition, the preferred healing of diabetic wounds confirmed the curative potential of iPSC-EVs, which was functionally achieved through immunoregulation in the induction of anti-inflammatory macrophage phenotypes induction. 109 Bioinspired nanovesicles (NVs) prepared through continuous cellular extrusion mode can be deemed as exosome mimetics that have comparable cell membranes and sizes. These new types of NVs are enriched with more proteins and RNAs than EVs, as well as exhibiting greater productivity.…”

Advances in the application of extracellular vesicles derived from three-dimensional culture of stem cells

“…In addition, in a glutamate-induced rat retinal injury model, adipose MSC-derived EVs were shown to reduce retinal excitotoxicity and markedly improve the morphological and functional abnormalities of the inner retinal layer [ 65 ]. Moreover, iPSC-derived EVs (iPSC-EVs) could promote wound repair in diabetic mice through anti-inflammatory immunomodulatory effects [ 66 ]. Compared with the natural application of SC-EVs, it is also possible to pre-treat the parental cells to obtain EVs with corresponding properties or to engineer EVs for drug loading and surface modification to obtain better therapeutic effects [ 67 ].…”