Immunomodulatory Effect of Adipose-Derived Stem Cells: The Cutting Edge of Clinical Application

Abstract

Adipose-derived stem cells (ASCs) represent a promising tool for soft tissue engineering as well as for clinical treatment of inflammatory and autoimmune pathologies. The well-characterized multi-differentiation potential and self-renewal properties of ASCs are coupled with their immunomodulatory ability in providing therapeutic efficacy. Yet, their impact in immune or inflammatory disorders might rely both on cell contactdependent mechanisms and paracrine effects, resulting in the release of various soluble factors that regulate immune cells functions. Despite the widespread use of ASCs in clinical trials addressing several pathologies, the pathophysiological mechanisms at the basis of their clinical use have been not yet fully investigated. In particular, a thorough analysis of ASC immunomodulatory potential is mandatory. Here we explore such molecular mechanisms involved in ASC immunomodulatory properties, emphasizing the relevance of the milieu composition. We review the potential clinical use of ASC secretome as a mediator for immunomodulation, with a focus on in vitro and in vivo environmental conditions affecting clinical outcome. We describe some potential strategies for optimization of ASCs immunomodulatory capacity in clinical settings, which act either on adult stem cells gene expression and local microenvironment. Finally, we discuss the limitations of both allogeneic and autologous ASC use, highlighting the issues to be fixed in order to significantly improve the efficacy of ASC-based cell therapy.

Co-Microencapsulation of Islets and MSC CellSaics, Mosaic-Like Aggregates of MSCs and Recombinant Peptide Pieces, and Therapeutic Effects of Their Subcutaneous Transplantation on Diabetes

“…It is known that MSCs secrete anti-inflammatory cytokines (IL-10, TGF-α, IDO, TSG-6, etc.) [15][16][17]31], and we have confirmed that MSC CellSaics secreted 3.1-fold more anti-inflammatory cytokine TSG-6 in response to concentration of inflammatory cytokine TNF-α than the MSC spheroids [20]. In reference [34], it is reported that transplantation of ALG-PLO microencapsulated islets trigger inflammation by increasing the TNF-α concentration at the transplantation site.…”

“…In contrast to spheroids, the spaces between the petaloid RCP pieces of the CellSaic allow for the sufficient penetration of substances into the cells, which effectively prevents cell death [13]. Mesenchymal stem cells (MSCs) are promising options as the cells comprising CellSaics for subcutaneous transplantation since they have revascularization, anti-inflammatory, and immunomodulatory abilities [14][15][16][17] and are known to enhance islet function when co-transplanted with them [18,19]. Our previous study demonstrated the continuous release of angiogenic factors and anti-inflammatory cytokines via a combination of MSCs and CellSaics (MSC CellSaics) [13,20].…”

Mesenchymal Stem Cell Therapy for Diabetic Kidney Disease: A Review of the Studies Using Syngeneic, Autologous, Allogeneic, and Xenogeneic Cells

“…These data suggest the possibility of developing a biobank of allogeneic MSCs for therapeutic purposes in several pathologies, since these cells lack the expression of class II MHC (Major Histocompatibility Complex) antigens and costimulatory molecules (CD80/B7.1 and CD86/B7.2) [ 39 ]. Noteworthily, the potential impact of donor-to-donor heterogeneity and the potential immunogenicity of allogeneic cells, depending on the culturing conditions and passages, the microenvironment, and the differentiation state, may alter the immunogenic phenotype, as recently reviewed [ 172 ].…”

Adipose-Derived Stem Cells from Obese Donors Polarize Macrophages and Microglia toward a Pro-Inflammatory Phenotype

“…Adipose tissue-derived stem cells (ASCs), a type of mesenchymal stem cell (MSC), possess significant anti-inflammatory and immunomodulatory properties that make them an attractive therapeutic option for numerous inflammatory diseases. ASCs exert their effects on the adaptive and innate immune system via the secretion of soluble molecules and extracellular vesicles (EVs), which alter the inflammatory microenvironment [ 1 , 2 , 3 , 4 ]. This is partially accomplished by transitioning activated macrophages from pro-inflammatory toward anti-inflammatory, pro-repair phenotypes [ 1 , 2 ].…”