Human mesenchymal stem cells respond to native but not oxidized damage associated molecular pattern molecules from necrotic (tumor) material

Abstract

Necrosis is a characteristic feature of advanced solid tumors. Released necrotic factors, also referred to as damage associated molecular patterns (DAMPs), are known to critically impact the tumor microenvironment by enhancing angiogenesis or influencing the immune response. We have recently shown that DAMPs can act as chemoattractants and activators of granulocytes. We demonstrate that necrotic material from both normal and tumor cells promotes proliferation and trafficking of human mesenchymal stem cells (MSCs). We characterize the protein high mobility group box 1 (HMGB1) as a crucial member of DAMPs within necrotic material. In addition, we show that DAMPs interfere with expression of indoleamine 2, 3-dioxygenase (IDO) in MSCs. The biological activity of necrotic material toward MSCs is abolished once these DAMPs are oxidized. MSCs found within tumor tissue can act as immunoregulatory cells and are able to promote tumor metastasis, thus playing a crucial role within the tumor microenvironment. Here, we reveal DAMPs to be crucial factors in the setting of MSC biology within the tumor microenvironment. The tumor microenvironment is characterized by reducing and hypoxic conditions that protect DAMPs from oxidation. Based on our results, oxidizing conditions should be considered for therapeutic approaches that target the tumor microenvironment.Key words: Chemotaxis . Damage associated molecular patterns . Mesenchymal stem cells . Proliferation . Supporting Information available online See accompanying Commentary by Pistoia and Raffaghello IntroductionRegardless of the origin and site of neoplastic cells, necrotic cell death is a characteristic feature of advanced solid tumor mainly due to three conditions: (i) inadequate nutrition supply to tumor cells as a consequence of imbalance between tumor growth and angiogenesis, (ii) the host's cytotoxic immune response to the tumor, and (iii) downregulation of programmed (apoptotic) cell death by the tumor itself. Released factors following necrotic cell death are also referred to as damage associated molecular patterns (DAMPs). DAMPs can critically impact the tumor microenvironment by enhancing angiogenesis or influencing [5,6]. MSCs are pluripotent progenitor cells that contribute to the maintenance and regeneration of a variety of connective tissues, including bone, adipose, cartilage, and muscle [7]. Although MSCs reside predominantly in the bone marrow, they are also distributed throughout many other tissues, where they are thought to serve as local sources of dormant stem cells [8]. The contributions of MSCs to tissue formation become apparent in cases of tissue remodelling after injury or chronic inflammation. These conditions are typically accompanied by mobilization of multipotent MSCs from bone marrow and their subsequent recruitment to the site of damage [8]. MSCs have been shown to contribute to the formation of fibrous scars after injury [9]. Systemically transferred MSCs have been described to migrate into colon carcinomas [10]. In the setting of wound he...

Necrotic cell-derived high mobility group box 1 attracts antigen-presenting cells but inhibits hepatocyte growth factor-mediated tropism of mesenchymal stem cells for apoptotic cell death

“…This observation appears to be in conflict with previous studies. 36,45,46 Interestingly, the HMGB1-driven migratory responses of MSC in these studies have either been independent of RAGE 36,46 or the type of receptor has not been assessed, 45 which could imply a possible role of HMGB1/ CXCL12 complexes. On the other hand, RAGE-mediated chemoattractive activity of HMGB1 has been documented for other stem and progenitor cells, including endothelial progenitor cells, 37 as well as for progeny of MSC-like smooth muscle cells 47 and fibroblasts.…”

S100A4 and Uric Acid Promote Mesenchymal Stromal Cell Induction of IL-10+/IDO+ Lymphocytes

“…We recently demonstrated, in a DC/ lymphocyte coculture assay, the immunosuppressive capacity of S100A4, S100-pulsed DCs also induced regulatory T cells that suppressed lymphocyte proliferation in allogeneic cocultures (3). We demonstrated that oxidation significantly reduces the bioactivity of lysed cells on MSCs (2). In addition to HMGB1, we have now identified S100A4 as another oxidation-sensitive DAMP that plays a crucial role in the biologic activity of necrotic material.…”

“…We have recently shown that necrosis-associated factors (DAMPs) from lysed cells can also promote the proliferation of MSCs (2), but once necrotic material was oxidized or preincubated with soluble RAGE, nominally blocking RAGE ligands (including S100A4 and HMGB1), the enhanced proliferative effect was significantly diminished (2).…”

“…Oxidation, however, limits the biologic activity of DAMPs (2). We now evaluated an oxidation-sensitive DAMP (S100A4) as well as a DAMP with high reducing potential (UA).…”

ATP promotes immunosuppressive capacities of mesenchymal stromal cells by enhancing the expression of indoleamine dioxygenase

“…These factors act as “danger” signals recruiting inflammatory cells, inducing inflammation (cytotoxic environment) on the one hand, but promoting wound healing processes (immunosuppressive environment), on the other. While wound healing is itself a self‐limiting process, advanced solid tumors—being “addicted to death”1—perpetually release DAMPs which promote recruitment of MSCs,2 enhance angiogenesis, and limit immunity 3. Thus, the tumor coopts the regenerative capacity of the host1, 4 resulting in tumor's own survival and proliferation.…”