clinical implications of basic research The new england journal of medicine n engl j med 364;12 nejm.org march 24, 2011 1174 In Utero Hematopoietic Stem-Cell Transplantation — A Match for Mom Ornella Parolini, Ph.D. Once researchers recognized that adult stem cells can generate multiple cell types and contribute to tissue homeostasis, it became conceivable to exploit this potential to treat genetic or acquired disorders characterized by tissue degeneration or organ dysfunction. The concept of regenera- tive medicine was thus born, with the general aim of transplanting donor stem cells to replace or repair defective cells of the host. Unfortunately, in the case of an HLA mis- match between donor and recipient, transplan- tation is hampered by the risks of immunologic recognition and rejection of the graft. However, a recent article by Nijagal and colleagues 1 re- vives the discussion of the potential advantages of transplanting stem cells into the fetus early in gestation. Because in utero stem-cell trans- plantation can be carried out when the immune system is immature, it provides the theoretical opportunity to induce fetal tolerance of the for- eign cells and thereby avoid rejection and the need for immunosuppressive therapy. For these reasons, this potential clinical approach is attrac- tive for any disorder that is amenable to stem- cell transplantation and that can be prenatally diagnosed. However, despite successful results of in utero transplantation in animal models, achieved for the most part with hematopoietic stem cells (HSCs), positive outcomes of this procedure in humans have been limited to cases of inherited immunodeficiency diseases. 2-4 One of the main hurdles to widespread application and success of in utero stem-cell transplanta- tion is the difficulty in achieving adequate levels of engraftment. Nijagal and colleagues tested their hypothe- sis that maternal cells trafficking into the fetus impede effective in utero stem-cell transplanta- tion by mounting a sort of “immune protection” of the fetus, in which maternal cells effect the rejection of cells allogeneic to both mother and fetus. Using mouse models, these researchers tested their hypothesis in a series of experi- ments to evaluate the role of the maternal im- mune response in limiting engraftment. First they found that in utero transplantation of fetal HSCs elicited an increase in trafficking of ma- ternal T cells to the fetal blood. To test the hy- pothesis that maternal cells play a pivotal role in the fetal engraftment of allogeneic cells, they transferred allogeneic fetal HSCs into fetuses of mothers with experimentally induced B-cell or T-cell deficiency (Fig. 1). Levels of engraftment were significantly higher in fetuses of mothers with T-cell deficiency than in fetuses of wild- type mothers or of mothers with B-cell deficiency. Finally, when in utero stem-cell transplantation was performed with HSCs matched to the mother, similar levels of engraftment were ob- served in fetal recipients of syngeneic and allo- geneic fetal grafts. The evidence put forward is clear and strik- ing, although further research is warranted to confirm these findings, as well as to determine whether maternal T cells are critical for the suc- cess of in utero stem-cell transplantation in other animal models. Differences in placentation be- tween animal species might predict differences in maternal-cell trafficking and thus the extent to which the observed phenomenon in mice is relevant to other animals. However, considering that the same types of hemochorial placentation and fetal–maternal chimerism have been de- scribed in humans, the conclusion of Nijagal et al. may be relevant to humans. The clinical relevance of this study lies in the potential for improving engraftment with the use of cells that are either harvested from or matched to the mother’s cells (Fig. 1). Although collect- ing stem cells from pregnant women presents