Decidual Stromal Cells from Placenta - Experimental and Clinical Studies

Ringdén, O.; Kaipe, H.; Erkers, T.; Nava, S.; Molldén, P.; Sadeghi, B.
June 2013
Cell Journal (Yakhteh);Summer 2013 Supplement 1, Vol. 15 Issue Sup 1, p13
Academic Journal
Objective: One of the most serious complications after hematopoietic stem cell transplantation is acute graftversus- host disease (GVHD), which develops when donor- derived T-cells recognize and become activated by alloreactive recipient tissue. We were the first to use bone marrow-derived mesenchymal stem cells (BM-MSCs) to reverse severe steroid-refractory acute GVHD and hemorrhagic cystitis. The fetus is protected against the mother's immune system by the fetal membrane. We wanted to explore if stromal cells from the placenta could be used for GVHD and tissue damage in a similar way as MSCs. Materials and Methods: We collected stromal cells from various parts of the placenta. To characterize these cells, we used fluorescence activated cell sorter (FACS). For functional analysis, mixed lymphocyte culture (MLC) and mitogen stimulation of human and mice cells were used. For studies of GVHD, we used B6 mice as donors and Balb/C mice as recipients of hematopoietic stem cell transplants. Patients with steroidrefractory acute GVHD were also included. Results: Stromal cells from the fetal membrane were easy to expand in vitro. We found that decidual stromal cells (DSCs) had the best immunosuppressive effect in vitro in MLC. Caryotyping of DSCs showed normal female karyotype. PCR showed that these cells were of female, maternal type. DCSs were positive for typical MSC markers, CD29, CD44, CD73, CD90 and CD105. DSCs were negative for hematopoietic markers, endothelial markers and epithelial markers. Unlike BM-MSCs, they were positive for PD-L1 and PD-L2 (negative regulation of co-stimulatory molecules). DSCs were also positive for CD49D, a marker for homing to inflammatory tissue (integrin). Indoleamine2,3-deoxygenase, prostaglandin E2, PD-L1 and interferon- • seemed to participate in the immunosuppressive mechanism by DSCs. DSCs promote CD4+ CD25+ FoxP3+ regulatory T-cell expansion in a contactdependent manner. Human DSCs inhibit mice MLC and also mice cells stimulated by phytohemaggluthinin. Human DSCs also inhibited mice cells stimulated by human blood lymphocytes. For Balb/C mice undergoing stem cell transplantation with B6 donors, GVHD was reduced if DSCs were added on day 3 after transplantation. Human DSCs also stimulated proliferation in xeno-immunized mice, but could also depress this reactivity in vitro. Among eight evaluable patients with severe steroid-refractory acute GVHD, two had a complete response, four had a partial response with an overall response rate of 75%. Two patients did not respond at all. Melena stopped in three patients with severe hemorrhagic diarrhea after treatment with DSCs. Among the patients treated with DSCs, three are long-term survivors. Conclusion: Stromal cells from the fetal membrane inhibit alloreactivity in vitro in MLC. They are of maternal origin, are safe to infuse to patients and they can inhibit and resolve GVHD in experimental animals and in patients. DSC therapy needs to be improved.


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