Data against a Common Assumption: Xenogeneic Mouse Models Can Be Used to Assay Suppression of Immunity by Human MSCs

Abstract

Much of what we know about immunology suggests that little is to be gained from experiments in which human cells are administered to immunocompetent mice. Multiple reports have demonstrated that this common assumption does not hold for experiments with human mesenchymal stem/stromal cells (hMSCs). The data demonstrate that hMSCs can suppress immune responses to a variety of stimuli in immunocompetent mice by a range of different mechanisms that are similar to those employed by mouse MSCs. Therefore, further experiments with hMSCs in mice will make it possible to generate preclinical data that will improve both the efficacy and safety of the clinical trials with the cells that are now in progress.

Keywords: immunomodulation; mesenchymal stem cells; mesenchymal stromal cells; xenogeneic models.

Figure 1

Summary of Major Differences between Expansion in Culture of mMSCs and hMSCs ^aPhinney and associates developed an elegant protocol for expanding mMSCs without transformation by first immunodepleting the cultures of hematopoietic cells and then culturing them under an atmosphere of 5% oxygen. ^bExpansion at low density to enrich early progenitor cells defined as rapidly self-replicating MSCs or RS cells described by Lee et al. and in references therein. ^cVaries with preparations of different bone marrow aspirates taken from the same donor at the same session.

Figure 2

Summary of Immune-Suppressive Effects of hMSCs in Mice (A) Data from experiments, in which 2 × 10 hMSCs were infused intravenously into immune-deficient mice (NOD/scid). The hMSCs were detected in tissues by qPCR assays for human-specific Alu sequences and by qRT-PCR assays specific for human GAPDH mRNA. For the RT-PCR assays, standards curves were prepared for each tissue (with hMSCs added to tissue from control mice) to correct for variability in extraction of mRNA and the efficiency of the polymerase reaction. (B) Data on hearts from experiments, in which 1 × 10 hMSCs were infused intravenously into immune-deficient mice (NOD/scid) right after permanent ligation of the left anterior descending coronary artery. Hearts were assayed as in (A). (A and B) from Lee et al. Reprinted with permission from Elsevier: Lee et al., Cell Stem Cell, 2009; 5: 59, Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6 (TNF-stimulated gene/protein-6). (C) Pharmokinetic analysis of the data in (A) by Parekkadan and Milwid. Solid blue line, apparent activity; dashed purple line, % of total cells remaining; dashed orange line, unit activity per cell; solid red line, therapeutic activity; dotted black line, minimum effective activity. Reprinted with permission from Annu. Rev. Biomed. Eng.: Parekkadan, B., and Milwid, J.M. Annu. Rev. Biomed. Eng. 2010;12:87, Mesenchymal stem cells as therapeutics. (D) In different immune models, the major immunosuppressive factors secreted by hMSCs were observed to be TSG-6, IL-1RA (IL-1 receptor antagonist), HO-1 (heme oxygenase 1), PGE2 (prostaglandin E2), TGF-β (tumor growth factor β), CCL2, IDO1 (indoleamine-pyrrole 2,3-dioxygenase 1), FasL (Fas ligand), or PD-L1 (programmed death-ligand 1). Most of the factors primarily altered cells of the innate immune system, such as monocytes/macrophages, MDSCs, or antigen presenting dendritic cells. Subsequent waves of cytokines then suppressed inflammation and altered T cells to either increase or decrease the ratio of Th1/Th17:Th2 responses.