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.

Transdifferentiation of bioencapsulated bone marrow cells into hepatocyte-like cells in the 90% hepatectomized rat model

“…There has been much recent research on the role of BMCs in liver regeneration and it has been shown that BMCs can transdifferentiate into hepatocyte‐like cells in vitro and in vivo 12, 15, 19–22. Some studies have been carried out to transplant BMCs 11, 23–27. Jang et al28 used a trans‐well membrane to separate cocultures of purified hematopoietic stem cells from injured liver tissue.…”

Reversine-treated fibroblasts acquire myogenic competence in vitro and in regenerating skeletal muscle

“…[3][4][5] In contrast with embryonic stem cells (ESCs), that nonetheless raise ethic controversy, the majority of human adult stem cells are difficult to expand in culture to the scale required for possible therapeutic applications without loss of pluripotency. In the past few years, several types of adult stem cells have been isolated from different sources and tested for their capability of rescuing the phenotype of several diseases, including muscular dystrophy.…”

Exogenous bone marrow cells do not rescue non‐irradiated mice from acute renal tubular damage caused by HgCl2, despite establishment of chimaerism and cell proliferation in bone marrow and spleen

“…2004; Vendrame et al . 2004) and has been reviewed in Fang & Poulsom (2003). For example, infusion with BMCs into non‐myeloablated recipients can improve cardiac function in mice with infarcted myocardium (Orlic et al .…”

“…2004; Vendrame et al . 2004) and reviewed in Fang & Poulsom (2003), including acute tubular damage (Kale et al . 2003; Lin et al .…”