Short-term memory of danger signals or environmental stimuli in mesenchymal stem cells: implications for therapeutic potential

Abstract

Mesenchymal stem/stromal cells (MSCs) possess some characteristics of immune cells, including a pro-inflammatory phenotype, an immunosuppressive phenotype, antibacterial properties and the expression of Toll-like receptor proteins. Here we show that, similar to immune cells, MSCs retain information from danger signals or environmental stimuli for a period of time. When treated with the pro-inflammatory factors lipopolysaccharide (LPS) or tumor necrosis factor-a (TNF-a), MSCs display increased expression of IL-6, IL-8 and MCP-1. Following re-plating and several rounds of cell division in the absence of stimulating factors, the expression of IL-6, IL-8 and MCP-1 remained higher than in untreated cells for over 7 days. A spike in cytokine secretion occurred when cells were exposed to a second round of stimulation. We primed MSCs with LPS and LPS-primed MSCs had better therapeutic efficacy at promoting skin flap survival in a diabetic rat model than did unprimed MSCs. Finally, we found that several microRNAs, including miR146a, miR150 and miR155, along with the modification of DNA by 5-hydroxymethylcytosine (5hmC), mediate the MSC response to LPS and TNF-a stimulation. Collectively, our data suggest that MSCs have a short-term memory of environmental signals, which may impact their therapeutic potential. Cellular & Molecular Immunology

LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b

“…Studies have found that the exposure of MSCs to the pharmacological agent lipopolysaccharide (LPS) can increase their trophic effects and functional properties to defend against the harsh inflammatory environment [ 11 – 13 ]. Liu et al have confirmed that LPS-primed MSCs have a superior therapeutic ability to preserve skin flap survival in a diabetic rat model compared to unprimed MSCs [ 14 ]. However, it remains unclear how LPS-preconditioned MSCs (LPS pre-MSCs) resolve chronic inflammation and whether they may function by accommodating macrophage polarization.…”

Concise Review: TLR Pathway-miRNA Interplay in Mesenchymal Stromal Cells: Regulatory Roles and Therapeutic Directions

“…This is corroborated by the finding that, in a similar fashion in mature human DCs, miR‐155 suppressed inflammatory cytokine production in response to LPS by targeting TAB2 . Interestingly, in another study with adipose tissue (AD)‐derived MSCs the increased levels of miR‐155 (and miR‐146a) after transient treatment with LPS or TNF‐α was retained for at least 5 days, suggesting that some miRNAs are involved in the regulation of a “short‐term memory” for danger signals .…”

New Insights in Candida albicans Innate Immunity at the Mucosa: Toxins, Epithelium, Metabolism, and Beyond

“…Although these innate immune memory mechanisms have mainly been described in monocytes/macrophages and other immune cell types (reviewed in Netea et al, 2016), new studies are beginning to show that non-immune cells are also able to develop these memory-like responses (Hamada et al, 2019), including mesenchymal stem cells (Liu et al, 2016), hematopoietic progenitors (Kaufmann et al, 2018;Mitroulis et al, 2018) and skin epithelial stem cells (Naik et al, 2017). Concerning epithelial cells at mucosal surfaces, there is significant evidence for a priming event driven in a morphologyindependent fashion.…”