Modified embryonic stem cells may prolong survival of surgical grafts

1. When stimulated with a variety of growth and inflammatory factors, embryonic stem cells (ESCs) took on a macrophage-like phenotype, which is associated with immune-suppression.

2. The stimulated ESCs (ES-SCs) appeared to prolong non-self graft survival in mice by suppressing immune cell activity at the graft site.

Evidence Rating Level: 3 (Average)

Study Rundown: Currently, patients who receive donor organ transplants must take immunosuppressive drugs indefinitely to prevent transplant rejection. While these drugs suppress a patients’ immune system response against the donor transplant, they also cause severe side effects such as increased chance of infection. Consequently, cell-based therapies are being investigated as an alternative immunosuppressive therapy. This study showed that ESCs, which have the potential to become many different types of cells, exhibit macrophage-like functions when stimulated with a defined cocktail of stimulatory factors. Macrophages are immune cells that can suppress inflammatory responses by other immune cells, particularly T cells. The study further showed administration of these ES-SCs increased graft survival in mice when the graft is from a separate mouse donor, or allogeneic source. In one exciting experiment, significantly more allogeneic heart muscle cell grafts derived from ESCs survived at four weeks when mice were treated with ES-SCs prior to transplantation.

Important to note, mice in this study were treated with a single dose of ES-SCs and graft survival was followed for less than one month. Thus, the long-term effects and benefits of ES-SCs remain undefined. Importantly, the ES-SC suppressive effect appeared to depend on the mouse donor type or breed, suggesting that this protective ability of the ESCs may be donor-dependant. Lastly, the process to create ES-SCs required 24 days; a more efficient process may be necessary to move these findings toward a clinical therapy. Despite these limitations, this pilot study demonstrates a novel cell-based therapy that may prevent immune system rejection of donor transplants.

Click to read the study in PLOS ONE

Relevant Reading: Immunogenicity of induced pluripotent stem cells

In-Depth [animal study]: In a 24-day process, ESCs were cultured with sequential treatment of growth factors and lipopolysaccharide, which promotes cell differentiation. The resulting ES-SCs displayed a macrophage-like morphology, as well as high expression of macrophage- and immunosuppression-associated genes. In an in vitro assay, ES-SCs significantly inhibited T cell proliferation (p < 0.01). Researchers then investigated T-cell inflammatory responses to cells of different donor mice following exposure to either ES-SCs or a no-cell control. While exposure to ES-SCs suppressed the immune response of the T cells to one allogeneic donor type (the 129 mouse), it did not suppress the response against another donor type (the BALB mouse).

The ability of ES-SCs to prolong graft survival was tested in a mouse model using two separate types of grafts. The first type of graft was a transplanted ESC-derived embryoid body. In mice pre-treated with saline, no allogeneic grafts survived by day 14 post-transplantation. In mice pre-treated with ES-SCs, 100% of grafts survived for 14 days, but 0% of grafts survived for 28 days. In the second set of transplant experiments, researchers used a graft of ESC-derived cardiomyocytes, which were more terminally differentiated than the embryoid bodies. In mice pre-treated with saline, 30% of allogeneic grafts survived for 14 days post-transplantation, and 10% of grafts survived for 28 days. When the mice were pre-treated with ES-SCs, 90% of grafts survived for 14 days, and 63% of grafts survived for 28 days. ES-SCs significantly improved cardiomyocyte graft survival outcome when compared to the saline control (p < 0.01). Histological analysis showed that T cell infiltration in the grafts was reduced by treatment with ES-SCs.

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