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Mar 22, 2012

Cheek Progenitor Cells Found to Be Vastly More Potent at Immunosuppression than Bone Marrow MSCs

  • A recently described progenitor cell (PC) type found in the mucosal layer of the cheek may have wide-ranging potential as a cell therapy for immune-related disorders, including the prevention of graft-versus-host reactions in organ transplant patients, scientists claim. The cells, known as oral mucosal lamina propria progenitor cells (OMLP-PCs) are a clonally derived PC population of neural crest origin, which can differentiate into both mesenchymal and neuronal cell types.

    A team at Cardiff University’s Cardiff Institute of Tissue Engineering and Repair in the U.K. first described the cell type in 2010. Now, working with colleagues at Huddinge University Hospital in Sweden, they describe in vitro studies demonstrating that OMLP-PCs are far more potent than bone marrow-derived mesenchymal stem cells (BBMSCs) at inhibiting unwanted immune reactions, and require only very low doses.

    Moreover, the team points out, a major advantage of OMLP-PCs over cells such as MSCs is that the cheek-derived cells can be clonally expanded, with each clone originating from a single cell. This allows production of homogeneous cell populations that are well-characterized and generate predictable and reproducible results. The Cardiff Institute’s Phil Stephens, M.D., and colleagues describe their findings in Stem Cells and Development in a paper titled “Oral Mucosal Progenitor Cells Are Potently Immunosuppressive in a Dose-Independent Manner.”

    The well-characterized immunosuppressive and immunoprivileged features of BBMSCs are being in clinical trials as allogeneic cell therapy for immune-related disorders, including acute and chronic graft-versus-host disease, and in hematopoietic stem cell (HSC) transplantation. One drawback of BBMSCs, however, is that harvesting the cells requires invasive procedures. The number of BMMSCs also decreases with age, the investigators point out.

    Previous work by the Cardiff team has demonstrated that OMLP-PCs have a similar cell surface marker expression profile to BMMSCs, in that they are CD90+ , CD105+ , CD166+ , CD44+ , CD34-,  and CD45-. Separate analyses have confirmed the cells are also CD29+ and CD73+. To evaluate whether OMLP-PCs may represent a more easily accessible source of immunosuppressive cells for potential therapeutic applications, the team carried out a series of in vitro studies using OMLP-PCs isolated from buccal mucosa biopsies taken from patients undergoing routine dental procedures. OMLP-PCs were isolated from the biopsies, separated by differential adhesion to fibronectin, and clonally expanded.

    Analysis of cell surface and specific intracellular expression of key markers of alloantigen presentation were measured by flow cytometry and, for HLA class II molecules, Western blotting. The OMLP-PCs were found to constitutively express HLA class I on their surface, which was upregulated slightly on exposure to IFN-γ. In contrast, there was no constitutive cell surface or intracellular expression of HLA class II. Intracellular expression of HLA class II was, however, visualized by Western blotting in response to IFN-γ exposure, and led to cell surface expression of HLA class II, but only after seven days. “These results demonstrate significant differences to those previously reported for BMMSCs that constitutively express intracellular HLA class II,” the team notes.

    Flow cytometry analyses confirmed that OMLP-PCs did not express FasL (CD178) or the costimulatory molecule CD40 and its ligand CD154, CD80, or CD86, either in the absence or presence of IFN-γ for seven days.

    To determine whether OMLP-PCs could suppress the proliferation of PBLs, the researchers applied one-way mixed lymphocyte culture (MLC) assays, and stimulated the cells with the T cell mitogen PHA.  The tests were carried out separately on OMLP-PCs that had been prestimulated using IFN-γ (to trigger cell surface HLA class II expression), and those that hadn’t been subjected to IFN-γ.

    The results from both MLC and mitogen assays demonstrated that the OMLP-PCs could completely inhibit PBL proliferation, “demonstrating the ability of OMLP-PCs to respond to both allogeneic and mitogenic stimuli,” the researchers write. Moreover, induction of HLA class II expression on the cell surface following prestimulation with IFN-γ had no effect on this inhibitory capacity, indicating that that OMLP-PC immunosuppression occurs via a HLA class II–independent mechanism. These results contrast with those obtained using BMMSCs, where pre-exposure to IFN-γ increases the inhibition of PBL proliferation.

    Interestingly, there was no difference in the levels of PBL inhibition when one-way MLC assays were set up with OMLP-PCs either in direct contact with the PBLs or separated by a membrane. This further suggested that OMLP-PCs can completely suppress the proliferation of PBLs through the release of soluble factors, again in a dose- and HLA class II-independent manner. Analyses demonstrated that OMLP-PC inhibition of PBL proliferation wasn’t linked with the induction of cell death, but instead appeared to protect PBLs from apoptosis. In other words, the immunosuppressive effects are apparently due to true inhibition, rather than simply due to the induction of apoptosis.

    “This is the first time that a PC population has been demonstrated to immunosuppress to this extent and in such a dose-independent manner,” the authors state. “These findings have implications in the clinical application of stem cell populations for both allogeneic tissue engineering applications as well as in the treatment of immune-related disorders such as GVHD where BMMSCs are currently the preferred cell source...These cells offer direct advantages over currently utilized BMMSCs in that not only would fewer cells be required to induce immunosuppression (hence a significant impact on scale-up and cost for development as a therapeutic) but cells can be reliably isolated from an easily accessible biopsy site with no/minimal scarring for the donor.”

     



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