Mesenchymal Stem Cell-Educated Macrophages Ameliorate LPS-Induced Systemic Response

Abstract

Both bone marrow and adipose-derived mesenchymal stem cells (ASCs) have immunomodulatory effects. The goal of this study was to determine whether ASCs-educated macrophages could directly ameliorate LPS-induced systemic response in a mouse model. Mouse peritoneal macrophages were cocultured with ASCs in a Transwell system for 2 days to educate macrophages. Mice were divided into 5 groups: control, LPS, LPS + ASCs, LPS + untreated macrophages, and LPS + educated macrophages. Educated macrophages decreased lung inflammation, weight loss, pulmonary edema, and inflammatory cytokine response. In vitro, ASCs increased expression of M2 macrophages independent of direct cell-to-cell contact when macrophages were treated with LPS or serum from patients with acute respiratory distress syndrome (ARDS). When macrophages were cultured with serum from ARDS patients who were treated with ASCs or placebo in our previous clinical trial, there was no difference in M2 macrophage levels before and after ASCs treatment indicating a suboptimal response to the treatment protocol. ASCs also reduced the levels of LPS-induced proinflammatory cytokines in vitro which were mimicked by IL-10 and blocked by antibodies for IL-10 and IL-10 receptor supporting the notion that educated macrophages exert their anti-inflammatory effects via IL-10-dependent mechanisms.

Human Mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE2-dependent mechanism

“…In a clinical trial with Adipose derived MSCs for correction of ARDS, an improvement of disease parameters were noted upon MSC transplantation. However no significant increase in M2 polarization was noted upon culture of patient macrophages with ARDS serum obtained from either control or MSC transplanted subjects indicating that human MSC could decipher unique programming instructions to human macrophages distinct from those existent at the mouse MSC/Macrophage interface21. Further distinct paracrine factors from different tissue specific MSC could influence immune outcomes in co-culture and transplant settings.…”

“…Further co-culture of mouse peritoneal macrophages with adipose derived MSC ex vivo and transplantation of these MSC educated macrophages ameliorated LPS induced systemic inflammation in mice. Though secretion of anti-inflammatory mediators such as IL-10 by MSC-educated macrophages has been proposed to mediate this effect the exact mechanisms of how MSCs educate macrophages to attenuate inflammation and facilitate repair is not understood2141.…”

“…Further the mouse macrophage-MSC interface could be very different from the human macrophage-human MSC interface due to key differences in macrophage biology in the human and mouse system44. Though MSC-educated peritoneal macrophages alleviated systemic inflammatory responses in LPS induced inflammation model, a parallel study to establish a similar concept in human macrophages from Acute respiratory distress syndrome (ARDS) did not exactly mimic mouse macrophage observations21. In a clinical trial with Adipose derived MSCs for correction of ARDS, an improvement of disease parameters were noted upon MSC transplantation.…”

“…Thus we hypothesize that the exact functional state of macrophage at the MSC interface could play a critical role in influencing the therapeutic outcome upon MSC transplantation. Previous evidences from mouse MSC/macrophage interaction studies indicate broad changes in M1/M2 balance during in vitro and in vivo interface192021 However, the exact relevance of human MSC- human macrophage cross-talk when interfaced with “distinct” macrophage functional modules is underappreciated.…”

Extracellular Vesicle-Educated Macrophages Promote Early Achilles Tendon Healing

“…A number of studies have examined the in vitro effects of MSCs as well as adipose‐derived stem cells (ASCs) on macrophage polarization . MSCs have been shown to inhibit M1 markers such as TNF‐α and iNOS, and promote M2 polarization .…”