Dynamic HoxB4-regulatory network during embryonic stem cell differentiation to hematopoietic cells.

Efficient in vitro generation of hematopoietic stem cells (HSCs) from embryonic stem cells (ESCs) holds great promise for cell-based therapies to treat hematologic diseases. To date, HoxB4 remains the most effective transcription factor (TF) the overexpression of which in ESCs confers long-term repopulating ability to ESC-derived HSCs. Despite its importance, the components and dynamics of the HoxB4 transcriptional regulatory network is poorly understood, hindering efforts to develop more efficient protocols for in vitro derivation of HSCs.

HOXB4-transduced embryonic stem cell-derived Lin-c-kit+ and Lin-Sca-1+ hematopoietic progenitors express H60 and are targeted by NK cells.

Embryonic stem (ES) cells are a novel source of cells, especially hematopoietic progenitor cells that can be used to treat degenerative diseases in humans. However, there is a need to determine how ES cell-derived progenitors are regulated by both the adaptive and innate immune systems post transplantation. In this study, we demonstrate that hematopoietic progenitor cells (HPCs) derived from mouse ES cells ectopically expressing HOXB4 fail to engraft long-term in the presence of NK cells.

Cell fusion of bone marrow cells and somatic cell reprogramming by embryonic stem cells.

Bone marrow transplantation is a curative treatment for many diseases, including leukemia, autoimmune diseases, and a number of immunodeficiencies. Recently, it was claimed that bone marrow cells transdifferentiate, a much desired property as bone marrow cells are abundant and therefore could be used in regenerative medicine to treat incurable chronic diseases. Using a Cre/loxP system, we studied cell fusion after bone marrow transplantation.

HOXB4 but not BMP4 confers self-renewal properties to ES-derived hematopoietic progenitor cells.

Background: Achieving transplantation tolerance remains an unresolved clinical challenge. Although bone marrow transplantation (BMT) induces mixed chimerism that establishes transplantation tolerance, the preconditioning regimens required for BMT to succeed are too prohibitive for routine use. Recently, embryonic stem (ES) cells have emerged as a potential alternative cell source to bone marrow cells.

ES-cell derived hematopoietic cells induce transplantation tolerance.

Background: Bone marrow cells induce stable mixed chimerism under appropriate conditioning of the host, mediating the induction of transplantation tolerance. However, their strong immunogenicity precludes routine use in clinical transplantation due to the need for harsh preconditioning and the requirement for toxic immunosuppression to prevent rejection and graft-versus-host disease. Alternatively, embryonic stem (ES) cells have emerged as a potential source of less immunogenic hematopoietic progenitor cells (HPCs).

Hematopoiesis and immunity of HOXB4-transduced embryonic stem cell-derived hematopoietic progenitor cells.

The ability of embryonic stem (ES) cells to form cells and tissues from all 3 germ layers can be exploited to generate cells that can be used to treat diseases. In particular, successful generation of hematopoietic cells from ES cells could provide safer and less immunogenic cells than bone marrow cells, which require severe host preconditioning when transplanted across major histocompatibility complex barriers. Here, we exploited the self-renewal properties of ectopically expressed HOXB4, a homeobox transcription factor, to generate hematopoietic progenitor cells (HPCs) that successfully induce high-level mixed chimerism and long-term engraftment in recipient mice.

Immunogenicity and engraftment of mouse embryonic stem cells in allogeneic recipients.

Embryonic stem cells (ESCs) are pluripotent and therefore able to differentiate both in vitro and in vivo into specialized tissues under appropriate conditions, a property that could be exploited for cellular therapies. However, the immunological nature of these cells in vivo has not been well understood. In vitro, mouse-derived ESCs fail to stimulate T cells, but they abrogate ongoing alloresponses by a process that requires cell-cell contact.

Recombinant dimeric MHC antigens protect cardiac allografts from rejection and visualize alloreactive T cells.

Monomeric and dimeric soluble major histocompatibility complex (MHC) molecules down-regulate activated T cells in an antigen-specific manner in vitro. This property could be exploited to modulate alloresponses in vivo but has remained difficult to demonstrate. Here, intraperitoneal infusion of a Lewis-derived rat MHC class I molecule, RT1.

Induction of stable mixed chimerism by embryonic stem cells requires functional Fas/FasL engagement.

Background: Recent data show the efficacy of embryonic stem cells (ESC) to engraft in allogeneic recipients without host pretreatment. This property is due to their low expression of major histocompatibility complex (MHC) class I antigens and lack of MHC class II expression. Here, we tested the hypothesis that the constitutive FasL expression by ESC is a requirement for their stable engraftment in allogeneic recipients.