Therapeutic potential of adipose-derived stem cell extracellular vesicles: from inflammation regulation to tissue repair

Abstract

Inflammation is a key pathological feature of many diseases, disrupting normal tissue structure and resulting in irreversible damage. Despite the need for effective inflammation control, current treatments, including stem cell therapies, remain insufficient. Recently, extracellular vesicles secreted by adipose-derived stem cells (ADSC-EVs) have garnered attention for their significant anti-inflammatory properties. As carriers of bioactive substances, these vesicles have demonstrated potent capabilities in modulating inflammation and promoting tissue repair in conditions such as rheumatoid arthritis, osteoarthritis, diabetes, cardiovascular diseases, stroke, and wound healing. Consequently, ADSC-EVs are emerging as promising alternatives to conventional ADSC-based therapies, offering advantages such as reduced risk of immune rejection, enhanced stability, and ease of storage and handling. However, the specific mechanisms by which ADSC-EVs regulate inflammation under pathological conditions are not fully understood. This review discusses the role of ADSC-EVs in inflammation control, their impact on disease prognosis, and their potential to promote tissue repair. Additionally, it provides insights into future clinical research focused on ADSC-EV therapies for inflammatory diseases, which overcome some limitations associated with cell-based therapies.

Keywords: Adipose-derived stem cell; Cell-free therapy; Extracellular vesicles; Inflammation control; Tissue repair.

Fig. 1

ADSC-EVs carry phosphorylated STAT3 and are engulfed by macrophages in white adipose tissue. Phosphorylated STAT3 induces macrophage polarization towards the M2 phenotype. M2 macrophages play an anti-inflammatory role and are crucial in the browning of white adipose tissue. They induce the SVF to produce more tyrosine hydroxylase and promote ADSCs to produce more lactate. Both actions collectively contribute to the browning of white adipose tissue

Fig. 2

ADSC-EVs are engulfed by cardiomyocytes, where miR-221/miR-222 bind to the mRNA of PUMA and ETS-1, inhibiting their expression. Additionally, miRNA-146a binds to the mRNA of EGR-1, suppressing its expression. Collectively, these actions inhibit cardiomyocyte hypertrophy and apoptosis. Furthermore, ADSC-EVs suppress the polarization of M0 macrophages to the M1 phenotype and promote their polarization to the M2 phenotype through activation of the S1P/SK1/S1PR signaling axis, thereby reducing inflammation and damage after myocardial infarction

Fig. 3

ADSC-EVs promote the regeneration of neurons and blood vessels after a stroke by releasing various bioactive molecules, including miR-146a, miR-21-5p, and STAT3 activators. miR-146a inhibits the NF-κB pathway, reducing the production of pro-inflammatory cytokines TNF-α and IL-1β. miR-21-5p promotes M2 macrophage polarization by inhibiting PTEN. STAT3 activation in macrophages promotes the expression of Arg-1, further supporting M2 polarization. Additionally, ADSC-EVs inhibit the p38 MAPK signaling pathway. These processes collectively result in decreased inflammation and enhanced nervous tissue repair