Abstract
Transplantation of allogeneic human embryonic stem cell-derived cardiac progenitors triggers an immune response. We assessed whether this response could be modulated by the concomitant use of adipose-derived stromal cells (ADSC). Peripheral blood mononuclear cells were collected from 40 patients with coronary artery disease (CAD) and nine healthy controls. Cardiac progenitors (CD15+ Mesp1+) were generated as already reported from the I6 cell line treated with bone morphogenetic protein (BMP)-2. Adipose-derived stromal cells were obtained from abdominal dermolipectomies. We assessed the proliferative response of peripheral lymphocytes from patients and controls to cardiac progenitors cultured on a monolayer of ADSC, to allogeneic lymphocytes in mixed lymphocyte culture and to the T cell mitogen phytohemaglutin A in presence or absence of ADSC. Cardiac progenitors cultured on a monolayer of ADSC triggered a proliferation of lymphocytes from both patients and controls albeit lower than that induced by allogeneic lymphocytes. When cultured alone, ADSC did not induce any proliferation of allogeneic lymphocytes. When added to cultures of lymphocytes, ADSC significantly inhibited the alloantigen or mitogen-induced proliferative response. Compared to healthy controls, lymphocytes from patients presenting CAD expressed a decreased proliferative capacity, in particular to mitogen-induced stimulation. Adipose-derived stromal cells express an immunomodulatory effect that limits both alloantigen and mitogen-induced lymphocyte responses. Furthermore, lymphocytes from patients with CAD are low responders to conventional stimuli, possibly because of their age and disease-associated treatment regimens. We propose that, in combination, these factors may limit the in vivo immunogenicity of cardiac progenitors co-implanted with ADSC in patients with CAD.
Highlights
Human embryonic stem cells and their derivatives have been proposed to be less immunogenic than adult cells [1,2,3]
Because adipose-derived stromal cells (ADSC) have been reported to exert mesenchymal stem cell-like immunomodulatory effects [8,9,10] and may improve graft viability through their trophic effects, we tested whether they could mitigate the response of human lymphocytes to various stimuli including stem cell-derived cardiac progenitors, alloantigens or the T cell mitogen phytohemaglutin A (PHA)
Lymphocyte response to alloantigens in mixed lymphocyte culture is inhibited by addition of ADSC
Summary
Human embryonic stem cells and their derivatives have been proposed to be less immunogenic than adult cells [1,2,3]. Compelling evidence has accumulated to suggest that transplantation of undifferentiated [4, 5] embryonic stem cells or of their cardiac-directed progeny [6] into infarcted myocardium triggers an immune response that represents a serious hurdle in the perspective of clinical applications [7]. Because ADSC have been reported to exert mesenchymal stem cell-like immunomodulatory effects [8,9,10] and may improve graft viability through their trophic effects, we tested whether they could mitigate the response of human lymphocytes to various stimuli including stem cell-derived cardiac progenitors, alloantigens or the T cell mitogen phytohemaglutin A (PHA). To approach as much as possible the clinical situation we compared lymphocytes from patients presenting CAD, potential recipients of cardiac progenitor transplants, with those of healthy controls
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