Primed mesenchymal stem cells package exosomes with metabolites associated with immunomodulation

Abstract

Mesenchymal stem cell (MSC) based therapies are currently being evaluated as a putative therapeutic in numerous human clinical trials. Recent reports have established that exosomes mediate much of the therapeutic properties of MSCs. Exosomes are nanovesicles which mediate intercellular communication, transmitting signals between cells which regulate a diverse range of biological processes. MSC-derived exosomes are packaged with numerous types of proteins and RNAs, however, their metabolomic and lipidomic profiles to date have not been well characterized. We previously reported that MSCs, in response to priming culture conditions that mimic the in vivo microenvironmental niche, substantially modulate cellular signaling and significantly increase the secretion of exosomes. Here we report that MSCs exposed to such priming conditions undergo glycolytic reprogramming, which homogenizes MSCs’ metabolomic profile. In addition, we establish that exosomes derive from primed MSCs are packaged with numerous metabolites that have been directly associated with immunomodulation, including M2 macrophage polarization and regulatory T lymphocyte induction.

Extracellular Vesicles Derived From Mesenchymal Stem Cells (MSC) in Regenerative Medicine: Applications in Skin Wound Healing

“…Thus, differences have been described between the secretome of the human bone-marrow mesenchymal stem cells (BM-MSC), adiposetissue stem cells (ATSC), and umbilical-cord perivascular cells (UCPC) (Pires et al, 2016). Cells grown under hypoxia produce exosomes with enhanced angiogenic, regenerative, and immunomodulating capacities (Li et al, 2015a;Han et al, 2019;Showalter et al, 2019). Besides, it has been recently described that even the type of culture as standard monolayer or as multilayers/globules (sometimes referred with the misleading names of 2D and 3D, respectively, since we live in a 3D world), may also modulate the properties of the exosomes produced by the MSC.…”

“…They include adenosine, arginine, aspartic acid, cholesterol, glutamine, nicotinamide, uridine diphosphate (UDP) N-acetylglucosamine (UDP-GlcNAc), 5'-deoxy-5'-methylthioadenosine (MTA), palmitic acid, and isoleucine. Curiously, such molecules have been associated to anti-inflammatory activities, M2 macrophage polarization, and induction of regulatory T lymphocytes (Showalter et al, 2019). Besides, the EV obtained from the MSC, after being exposed to inflammatory cytokines (IFN-g and TNFa) for 40-48 h, inhibited the proliferation of B lymphocytes and natural killer (NK) cells, after being intaken by them (Di Trapani et al, 2016).…”

Preclinical translation of exosomes derived from mesenchymal stem/stromal cells

“…4 There are likely several reasons for such differences observed between MSC preclinical and clinical studies such as potency, consistency and scale-up manufacturing issues which have been reviewed elsewhere. 4,5 MSCs' therapeutic effects are generally thought to be mediated through the secretion of a variety of factors including canonical secretory proteins such as cytokines and growth factors, as well as exosomes [6][7][8][9][10] (Figure 1). MSCs act as a localized delivery system by secreting such factors, which then in turn affect the physiology of both adjacent and distant responder cells.…”

Unraveling the Molecular Signature of Extracellular Vesicles From Endometrial-Derived Mesenchymal Stem Cells: Potential Modulatory Effects and Therapeutic Applications

“…This concept has been recently reviewed by Yin et al (2019) and the idea of MSCs priming has been extrapolated to the production of licensed EVs. Several examples can be found in bibliography: exosomes from Interleukin 1β-primed MSCs expressed miR-146a to induce M2 polarization (Song et al, 2017); EVs from TNFα/IFNγ-primed MSCs were found to enhance the immunomodulatory activity of MSCs by altering the COX2/PGE2 pathway (Harting et al, 2018); furthermore, it was proved that exosomes from MSCs under low oxygen conditions produced exosomes with a higher pro-mitotic effect (Yuan et al, 2019), and immunomodulatory potential (Showalter et al, 2019).…”