Abstract
Understanding how embryonic stem cells and their derivatives interact with the adult host immune system is critical to developing their therapeutic potential. Murine embryonic stem cell-derived hematopoietic progenitors (ESHPs) were generated via coculture with the bone marrow stromal cell line, OP9, and then transplanted into NOD.SCID.Common Gamma Chain (NSG) knockout mice, which lack B, T, and natural killer cells. Compared to control mice transplanted with adult lineage-negative bone marrow (Lin− BM) progenitors, ESHP-transplanted mice attained a low but significant level of donor hematopoietic chimerism. Based on our previous studies, we hypothesized that macrophages might contribute to the low engraftment of ESHPs in vivo. Enlarged spleens were observed in ESHP-transplanted mice and found to contain higher numbers of host F4/80+ macrophages compared to BM-transplanted controls. In vivo depletion of host macrophages using clodronate-loaded liposomes improved the ESHP-derived hematopoietic chimerism in the spleen but not in the BM. F4/80+ macrophages demonstrated a striking propensity to phagocytose ESHP targets in vitro. Taken together, these results suggest that macrophages are a barrier to both syngeneic and allogeneic ESHP engraftment in vivo.
Highlights
Pluripotent embryonic stem cells (ESCs) have the potential to differentiate into any cell in the adult body, making them an ideal source of cells for tissue regeneration when other options are absent [1]
Transplantation of in vitro-derived Embryonic stem cell-derived hematopoietic progenitor hematopoietic stem cells (HSCs) (ESHP) into adult mouse hosts has not led to high levels of donor chimerism or long-term engraftment without transgenesis [8, 12]
Previous studies have shown the definitive mouse hematopoietic progenitors in the embryo express CD41 and transition through CD41+ CD45−, CD41+ CD45+, and CD41− CD45+ stages of maturation [25, 26], and we previously showed that ESHPs with these phenotypes could be generated using a coculture system on the OP9 bone marrow stromal cell line [21]
Summary
Pluripotent embryonic stem cells (ESCs) have the potential to differentiate into any cell in the adult body, making them an ideal source of cells for tissue regeneration when other options are absent [1]. Embryonic stem cell-derived hematopoietic progenitors (ESHPs), as well as a variety of terminally differentiated hematopoietic cells, can be cultured in vitro [6, 7], and ESHPs express markers commonly found on natural adult and embryonic hematopoietic stem and progenitor cell populations [8, 9]. We previously showed that macrophages from the 129 and Balb/c mouse strains preferentially phagocytosed ESHPs in vitro [21]. We extend those findings and present evidence which supports that host macrophages are an innate immune barrier to ESHP engraftment in vivo
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