Extracellular Vesicles Isolated from Mesenchymal Stromal Cells Primed with Hypoxia: Novel Strategy in Regenerative Medicine

Abstract

: Mesenchymal stromal cells (MSCs) regulate other cell types through a strong paracrine component called the secretome, comprising of several bioactive entities. The composition of the MSCs’ secretome is dependent upon the microenvironment in which they thrive, and hence, it could be altered by pre-conditioning the MSCs during in vitro culture. The primary aim of this review is to discuss various strategies that are being used for pre-conditioning of MSCs, also known as “priming of MSCs”, in the context of improving their therapeutic potential. Several studies have underscored the importance of extracellular vesicles (EVs) derived from primed MSCs in improving their efficacy in the treatment of various diseases. We have previously shown that co-culturing hematopoietic stem cells (HSCs) with hypoxiaprimed MSCs improves their engraftment potential. Now the question we pose is would priming of MSCs with hypoxiafavorably alter theirsecretome and would this altered secretome work as effectively as the cell to cell contact did? Here we review the current strategies of using the secretome, specifically the EVs (microvesicles and exosomes), collected from the primed MSCs with the intention of expanding HSCs ex vivo. We speculate that an effective priming of MSCs in vitrocould modulate the molecular profile of their secretome, which could eventually be used as a cell-free biologic in clinical settings.

Secretome derived from mesenchymal stromal cells primed with neurotrophic factors rescues Neuro-2a cells from endoplasmic reticulum stress-mediated loss of neurogenesis.

“…In independent studies, we have also demonstrated that MVs secreted by the MSCs boost the engraftment ability of HSCs, rejuvenate aged HSCs, and enhances the ability of HSCs to expand in vitro [17], [20], [21], [58]. Based upon these ndings, we are currently investigating the differential role of MSC CM-derived MVs and exosomes in enhancing the ex vivo expansion potential and in vivo engraftment potential of HSCs.…”

“…In ammation is one of the major factors responsible for the pathogenesis of ND Previously, we have reported the importance of MSCs and their secretome as potential therapeutics for ND[16], [24] as well as for improving the ex vivo expansion of HSCs [17], [21]. Presently, researchers are taking a step forward by adopting priming strategies to enhance the regenerative potential of MSCs and their secretome [18].…”

“…Presently, researchers are taking a step forward by adopting priming strategies to enhance the regenerative potential of MSCs and their secretome [18]. We have also previously deliberated that exposing MSCs to different factors like growth factors, hypoxia, cytokines, and pharmacological agents could improve the therapeutic potential of the MSC secretome [17], [20], [21]. Moreover, Lee et al have demonstrated that the CM from LPSprimed adipose-derived stem cells (ASC) was able to improve liver regeneration and function in both in vivo (BALB/c mice) and in vitro (mouse hepatocyte cell line AML12) conditions, thus highlighting the importance of priming [14].…”

“…Hence, the focus has now shifted towards the MSC secretome, which is enriched in several soluble factors, including cytokines, chemokines, immunomodulatory molecules, growth factors, and membrane-bound extracellular vesicles (EVs) [15]. Our earlier reports have emphasized the regenerative potential of the soluble and membrane-bound fraction of the MSC secretome [16], [17]. Moreover, other studies have reported that priming MSCs with different factors like cytokines, growth factors, and pharmacological factors can modulate the therapeutic potential of MSCs, thereby further underscoring their importance in regenerative medicine [18], [19].…”

Bio-Pulsed Stimulation Effectively Improves the Production of Avian Mesenchymal Stem Cell-Derived Extracellular Vesicles That Enhance the Bioactivity of Skin Fibroblasts and Hair Follicle Cells

“…Cell priming (here called biochemical pulse pattern, abbreviated as bio-pulsed) involves preparing cells for lineage-specific differentiation or conferring the cells with specific functions through cell activation, molecular signaling activation, genetic or epigenetic modifications, and morphology/phenotype alterations. Recently, studies have reported that the composition of the MSCs’ extracellular vesicles or exosomes is dependent upon the microenvironment in which they thrive, and hence it can be altered by pre-conditioning or priming the MSCs during in vitro culture [ 25 ]. MSCs were primed with pro-inflammatory cytokines or hypoxia; primed-MSCs derived extracellular vesicles or exosomes that were isolated and reported with special functions, such as anti-inflammation or better therapeutic efficiency [ 26 , 27 ].…”