Stem cells from any source are exciting, both as models of developmental biology and for their promise in treating human disease.
Their properties mean it is feasible to contemplate isolating stem cells from the body, expanding them under cell culture conditions, directing their proliferation with growth factors and then transplanting them or their progeny into patients of all ages for clinical gain.
In this way stem cells might in future be used to alleviate degenerative disorders, replace diseased or failing tissues with engineered substitutes, and correct genetic disease.
HSC have already been proven permanently and clonally to produce all cell types of blood and the immune system in engrafted hosts.
MSC might be applied therapeutically for the correction of disorders of mesenchymal origin and further potential therapeutic application is based on their ability to enhance engraftment of HSC after co-transplantation.
Whereas fetal stem cells could theoretically be used in place of stem cells derived from adult tissues for most applications, there are some areas where they may have specific advantages, as outlined below.
In utero transplantation
In utero transplantation of allogeneic stem cells is a novel approach to overcome the limitations of postnatal therapy: including severe treatment-associated morbidity and pre-existing organ damage that develops before birth.
Stem cell transplantation in early intrauterine life to correct genetic defects has several advantages and using fetal rather than adult stem cells might provide further benefits as fetal cells have a distinct competitive advantage over adult cells.
Early establishment of donor stem cell engraftment prenatally might prevent or reduce the pathology associated with the underlying disorder still further.
It is therefore important to understand the relative engraftment efficiency of different sources of fetal cells, which probably depends on intrinsic differences in cytokine requirements as well as extrinsic signals that differ in the fetal versus the adult microenvironment.
The initial targets chosen for in utero stem cell transplantation were HSC, not only because of their well-established proliferative and multilineage potential but also because of the years of clinical experience in adult transplantation.
To date, most attempts at HSC transplantation in utero have failed because the mid-trimester fetus is immunocompetent and rejects allogeneic cells.
This problem might be obviated by earlier transplantation, before the loss of tolerance.
Despite advances in cord sampling techniques for early fetal blood collection in ongoing pregnancies, the low yield of HSC in the late first trimester, together with their limited expandability, makes this approach problematic.
By contrast, adult MSC engraft widely in animal in utero transplantation models and appear to have unique immunological characteristics, which could allow engraftment irrespective of gestational age and immune competence.
When transplanted in utero into fetal sheep, fetal MSC engraft-albeit at low level-into multiple organ compartments and co-transplantation of adult MSC has been shown to enhance engraftment of HSC in utero in animal models, suggesting that cotransplantation of fetal MSC might also result in accelerated haemopoietic engraftment.
Fetal liver cells have already been used successfully to treat a fetus with X-linked severe combined immunodeficiency in utero.
Stem cells have considerable utility as vehicles for gene therapy because they are self-renewing, thus precluding the need for repeated administration of the gene.
Ex vivo gene therapy uses autologous HSC that are obtained first from the fetus, transduced in vitro and then transplanted back to the fetus.
Results from postnatal gene therapy trials now prove the clinical effectiveness of this approach, although gene therapy is under scrutiny since the recent reports of two children-developing leukemia following ex vivo postnatal gene therapy, presumably as a result of the viral vector disrupting an oncogene.
Other concerns are transgene expression in tissues other than the target tissue and inadvertent transfer into germline cells.
The biological advantages of targeting fetal MSC over HSC for autologous gene therapy include their higher proliferative capacity, greater transduction efficiency, ready expandability, reduced immunogenicity, ability to engraft and differentiate into most tissue types and ability to be targeted via ligands to specific tissue types.
This approach has the potential to cure quite a number of genetic diseases such as the mucopolysaccharidoses, the cerebral gangliosidoses, the leucodystrophies, osteogenesis imperfecta and muscular dystrophy.
Non-invasive prenatal diagnosis
Fetal stem cells cross into maternal blood during pregnancy and thus represent a potential non-invasive source of fetal genetic material for prenatal diagnosis.
Research in this area has been hampered by the lack of cell types unique to fetal blood and the low frequency of fetal cells trafficking across the placenta in early pregnancy.
The disparate range of cell types that traffic into the maternal bloodstream includes HSC and MSC.
Fetal haemopoietic progenitors have been demonstrated in the maternal circulation from early gestation onwards; however, they are difficult to distinguish from maternal circulating progenitors and most groups have been unable to expand the fetal cells sufficiently in vitro for clinical application.
Fetal MSC, which circulate in first trimester fetal blood, have been proposed as an alternative target cell for non-invasive prenatal diagnosis because they appear to have no counterpart in adult blood and can be clonally expanded into a pure source of fetal cells.
However, although fetal MSC are likely to cross the placenta based both on theoretical considerations and on our group's findings that fetal MSC are detectable in a small proportion of maternal blood samples, they appear to circulate at very low numbers, making any application in the field of non-invasive prenatal diagnosis unlikely.
The persistence of fetal cells for years in maternal tissues, known as fetomaternal microchimerism, has been implicated in autoimmune disease through graft-versus-host (GVH)-like responses.
However, the frequency of fetomaternal microchimerism after normal pregnancy and the cell type responsible is unknown.
One explanation for the apparent low frequency of fetal MSC in circulating maternal blood during pregnancy is engraftment in maternal tissues such as bone marrow soon after transplacental passage.
Expression of cell adhesion molecules, lack of expression of HLA class II antigens, along with the adherent properties of MSC in vivo, suggests that MSC can disperse widely and implant in connective tissues.
Adult bone-marrow-derived MSC readily engraft in most organs in animal models and preferentially home to bone marrow after infusion, whereas fetal MSC engraft diffusely after xenotransplantation in utero.
MSC therefore seem the most likely fetal cell type to persist in maternal tissues.
Recently it has been identified male fetal MSC in postreproductive female bone marrow up to 50 years after pregnancy in a group of women who had sons.