Molecular Genetic and Immune Functional Responses Distinguish Bone Marrow Mesenchymal Stromal Cells from Hepatic Stellate Cells

Abstract

Defining the immune physiology of culture-adapted mesenchymal stromal cells (MSCs) derived from distinct tissue compartments informs their potential utility as pharmaceuticals. Here, we have investigated the comparative immune plasticity of MSCs and hepatic stellate cells (HeSCs) isolated from human and murine bone marrow (BM) and liver, respectively. Although both BM-MSCs and HeSCs share mesenchymal phenotype and overall molecular genetic responses to inflammatory cues, HeSCs differ from BM-MSCs in a meaningful manner. We show that cultureadapted HeSCs express substantially higher levels of hepatocyte growth factor (HGF), matrix metalloproteinase-1, and chemokine (C C motif) ligand 2 (CCL2) than BM-MSCs. Both human BM-MSCs and HeSCs inhibit T-cell proliferation by a shared indoleamine 2,3-dioxygenase (IDO)dependent mechanism. However, HeSCs are distinct from BM-MSCs by their significant differential expression of HGF, CCL2, IL-8, CCL11, and GMCSF when cocultured with and/or without activated peripheral blood mononuclear cells. We have investigated MSCs and HeSCs derived from murine systems to describe interspecies comparability. Murine BM-MSCs inhibit T-cell proliferation through inducible nitric oxide synthase (iNOS) but not IDO. However, murine HeSCs inhibit T-cell proliferation through a mechanism distinct from either IDO or iNOS. Altogether, these results suggest that although culture-adapted BM-MSCs and HeSCs display a similar phenotype, their secretome and immune plasticity are in part distinct likely mirroring their tissular origins. In addition, the discordance in immune biology between mouse and human sourced HeSC and BM-MSCs speaks to the importance of comparative biology when interrogating rodent systems for human translational insights.The clinical use of mesenchymal stromal cells is expanding at a brisk pace. However, ambiguity still exists on the identity and function of mesenchymal cells from differential tissue sources. This study investigates the comparative biology mesenchymal stromal cells and hepatic stellate cells from bone marrow and liver. The data demonstrated that molecular genetic and immune functional responses distinguish their immune physiology. In addition, differences in the immunosuppressive pathways of these cell types between murine and of human origin suggest that careful considerations are required for the clinical translation of animal studies of into the human immune physiology.

The Role of Nitric Oxide in Cancer: Master Regulator or NOt?

“…Thus, NO exerts widely different impacts on the recruitment of myeloid and lymphoid-derived cells, thereby restricting the capacity of iNOS inhibition to restore immune function [ 225 ]. In considering the role of NO in immunomodulation it is also important to note that species specific differences exist in NO fluxes from iNOS, which may impact the roles of iNOS in immune cell modulation by different cell types including mesenchymal stromal cells and macrophages [ 226 , 227 , 228 ]. A more detailed review on the role of NO in macrophages and cancer is provided in [ 229 ].…”

Are Liver Pericytes Just Precursors of Myofibroblasts in Hepatic Diseases? Insights from the Crosstalk between Perivascular and Inflammatory Cells in Liver Injury and Repair

“…Therefore, pericytes are postulated to become activated after tissue injury and, in this activated, proliferative state, secrete paracrine molecules that reduce inflammation and apoptosis [89,90]. The similarities between cultured pericytes and MSCs extend to mesenchymal differentiation ability [84,87,91] and suppression of activated T cells, as demonstrated for cultured pericytes from the retina [92], adipose tissue [87], and liver (HSCs) [91]. Another important similarity between MSCs and cultured HSCs is their ability to stimulate monocytes to develop into alternatively activated macrophages characterized by the production of high amounts of TGF-β in vitro [93,94].…”

Transcriptome profiles acquired during cell expansion and licensing validate mesenchymal stromal cell lineage genes

“…Mesenchymal stromal cells (MSC) exhibit phenotypic and functional heterogeneity related to tissue origin, donor demographics, and processing protocols. Current metrics to establish MSC identity include plastic adherence, cell surface phenotyping, and tri-lineage differentiation [ 1 ], which do not clearly distinguish MSCs from other stromal resident cells such as fibroblasts [ 2 ] or hepatic stellate cells [ 3 ]. Two research groups recently performed deep integrative analysis of publicly available transcriptomics data for multiple MSC types compared to other stem and stromal cells to generate MSC-specific signatures [ 4 , 5 ].…”