Cell-based therapies for birth defects: a role for adult stem cell plasticity?

Abstract

Cell therapy can offer a reasonable approach to the treatment of specific birth defects, particularly those for which hematopoietic stem cells (HSCs) can be used to restore (even partially) the number of cells, protein levels, or enzyme activity. Relatively few clinical experiences have been published on this subject, but when a natural selective advantage exists for the cell graft, a degree of "rescue" is possible. Strategies have been developed to confer a selective advantage through genetic engineering of donor cells, and this approach may prove valuable in the treatment of birth defects, as it is in hematological malignancy. Stem cell (SC) plasticity, or transdifferentiation, may offer another route for delivery of cells to established or developing organs. A wide variety of studies support the concept that adult tissue-specific SCs can, if displaced from their normal niche to another, be reprogrammed to produce cell types appropriate to their new environment. Clinical observations reveal that persistent tissue microchimerism develops not only in blood lineages after transfusion, but also in thyroid follicular epithelium via transplacental exchange. In addition, hepatic and renal parenchyma also become chimeric following allografts or bone marrow transplantation (BMT). Experimental models indicate that a renal glomerulosclerosis phenotype can be transferred by grafting whole BM, and that a severe liver disorder in fah-/- mice can be overcome by grafting HSCs and then exerting a selection pressure. It may be possible in the future to exploit the ability of adult SCs to contribute to diverse tissues; however, our understanding of the processes involved is at a very early stage.