In-utero stem cell transplantation: clinical use and therapeutic potential.
Marco De SantisCarmen De LucaIlenia MappaEleonora CesariTomasella QuattrocchiTerryann SpagnuoloDaniela ViscontiGiuseppe NoiaAlessandro Caruso
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Abstract:
Early evidence suggests that in-utero stem cell transplantation represents a new therapeutic strategy for different congenital disease. Moreover, gene therapy constitutes one of the most promising new approach to treat a wide spectrum of genetic disorders. It was shown that the fetus could represent an ideal recipient because of his immunologic early naiveté in gestation that reduces the risk of immunoreactions. Clinical experience in human fetus was performed in order to treat immunodeficiency and metabolic disorders, hemoglobinopathies and some other genetic diseases. Use of alternative source (i.e., cord blood, placenta, membrane, amniotic fluid, fetal tissue) of stem cell transplanted has been only one of the several strategies to improve donor cell advantages on host stem cell. The present review focused on the clinical use and therapeutic potential of in-utero stem cell transplantation, reporting the outcome of human cases treated and the limits of this therapy and possible future applications.Keywords:
Stem Cell Therapy
Cord blood
Cell therapy
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Successful in utero stem cell transplantations with hematopoietic or other stem cells should represent a major step forward in the management of patients with congenital, hematological, metabolic, and immunological disorders. The possibility of performing cell transplantations with stem cells across histoincompatibility barriers without chemotherapy has great potential for both pre and postnatal transplantations. The present article includes an overview of this topic with special reference to different animal models and the experience in humans in regard to fetal stem cell transplantations.
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Stem Cell Therapy
Cell therapy
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Over the past 10 years, we have become involved in a new research effort and an increasing scientific interest in the field of stem cell-based therapy. We are therefore able to describe different areas in which stem cell research can be applied and developed in gynecology and obstetrics. I) Hematopoietic stem cells have been used to set up therapeutic strategies for the treatment of gynecological solid tumors such as ovarian cancer. In this context different autologous or allogeneic transplantation approaches have been proposed and clinically investigated. II) Umbilical cord blood, which was often considered a waste material of the delivery, actually represents a precious source of stem cells that can be used for cell-based treatments of malignancies and inherited diseases. III) A feto-maternal cell traffic has recently been demonstrated through the placental barrier during pregnancy. This cellular exchange also includes stem cells from the fetus, which can generate microchimerisms in the mother and contribute to tissue repair mechanisms in different maternal organs. IV) Stem cells can be used for prenatal transplantation to treat different severe congenital diseases of the fetus. Nevertheless, several problems need to be solved to achieve an efficient in utero stem cell transplantation. Recent reports have pointed out the importance of timing in prenatal stem cell transplantation procedures and have shown the advantage of an early stem cell injection. An ultrasound-guided intracelomic approach could allow this possibility.
Cord blood
Placenta cord banking
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In utero transplantation of hematopoietic stem cells is a most promising fetal therapy. The aim is to treat a genetic disease prenatally before the onset of irreversible organ damage. As the fetus is immunoincompetent in the first and early second trimester of pregnancy and thus tolerant to foreign antigen, engraftment of transplanted stem cells is possible without rejection and without the need for immunosuppression. Additionally, there is enough space available in the fetal bone marrow for the homing of transplanted stem cells, and the intrauterine environment is protective for the fetus, thus typical complications of postnatal transplantation like graft rejection could be avoided. Good results of in utero treatment of severe congenital immunodeficiencies have been achieved in different animal models as well as in humans. No success, however, has been reported as yet in genetic diseases without immunodeficiency, mainly because it seems to be difficult to achieve a clinically significant level of chimerism. Ongoing research projects are focussed on the search for alternative stem cell sources like umbilical cord blood or fetal liver, optimizing the in vitro stem cell processing by using special enrichment techniques, adding early growth factors to the transplant or expanding stem cells ex vivo and finding the ideal stem cell dose. In non-immunodeficient recipients the "window of opportunity" seems to be exclusively at the end of the first trimester; thus early administration of the transplant is mandatory. Induction of tolerance against donor cells is possible, though the clinical relevance for postnatal transplantation remains to be proven.
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Inherited severe genetic diseases are rare but devastating disorders associated with vast morbidity and mortality. Currently there is no cure for many of these diseases, but merely pharmacological therapies replacing the missing gene product or inhibiting the progressing pathology of the disease. Stem cell transplantation has the possibility to restore the defect permanently and hematopoietic stem cell transplantation (HSCT) is today used postnatally to cure sickle-cell disease, severe combined immunodeficiency (SCID), and other immune disorders [1, 2]. However, the pathology is progressing with sustained morbidity during fetal life and the disease may already be manifested at birth.
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Stem Cell Therapy
Hematopoietic stem cell
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Fetal stem-cell transplantation is an attractive approach to the treatment of a variety of hematological, metabolic and immunological diseases before birth. The possibility of delivering a large number of cells in an early stage of life, and of taking advantage of normal fetal stem-cell migration and development, is promising. During fetal life, the capacity to mount an immune response to allogeneic cells is impaired compared with adult life. This provides an opportunity to induce tolerance to alloantigens without the need for myeloablation, although there are possible immune barriers to foreign cells in the fetus.
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