IN UTERO TRANSPLANTATION OF HUMAN CELLS INTO PRIMATES

Project: Research project

Project Details

Description

The in utero transplantation of hematopoietic stem cells (HSCs) holds
considerable promise as a therapeutic approach to correct a variety of
prenatally diagnosed genetic disorders of hematopoiesis and immune
function. A number of animal model systems have demonstrated the feasi-
bility of transplanting immunologically naive donor cells into preimmune
allogeneic and xenogeneic recipients. The transplantation of early
gestation fetal liver cells and CD34+ adult bone marrow cells has been
associated with long-term donor engraftment and the absence of any serious
immunological sequelae. In human-sheep chimeras, sustained human
hematopoiesis is observed however, relatively low levels of engraftment of
human cells are achieved. These low levels of circulating donor cells may
in part be due to the presence of a suboptimal hematopoietic
microenvironment for the development of human progenitor cells. This
hypothesis is supported by the observation that the administration of
human hematopoietic growth factors to human-sheep chimeras significantly
increases the number of circulating human cells in the peripheral blood.
We postulate that the phylogenetic proximity of nonhuman primates to man
will provide a more favorable hematopoietic microenvironment for cell-cell
interactions and cross-reactive growth factor activity supporting long-
term multilineage hematopoiesis. The optimal tissue source and phenotype
of human HSCs for in utero transplantation remains unknown. In addition,
the functional activity of the differentiated progeny of engrafted donor
cells has yet to be determined. These parameters will need to be defined
to facilitate the rational design of clinical trials based on this
technology. This proposal will focus on testing the developmental
potential of human fetal hematopoietic stem cells following in utero
transplantation in a nonhuman primate model system. Specifically we
propose to: a) establish long-term human hematopoietic reconstitution of
nonhuman primates by in utero transplantation of CD34+ cells from the
fetal bone marrow and liver; b) evaluate the developmental potential of
phenotypically defined candidate human HSCs in the setting of in utero
transplantation and c) determine the immunological function of engrafted
human cells in human-primate chimeras. Ultimately, the results of these
studies may help to define the optimal source of human fetal HSCs for the
development of in utero transplantation protocols for the treatment of
genetic diseases in man.
StatusFinished
Effective start/end date8/5/943/31/99

Funding

  • National Institutes of Health: $87,779.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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