Gi Stem Cell Plasticity

Adult stem cells within many tissues are now known to have far higher levels of plasticity than previously thought. The adult hema-topoietic bone marrow stem cell differentiates into blood cell lineages and can transdifferentiate into many different cell types including hepatocytes (Petersen et al., 1999; Alison et al., 2000; Lagasse et al., 2000; Thiese et al., 2000), biliary epithelial cells (Thiese et al., 2000), endothelial cells (Gao et al., 2001; Lagaaij et al., 2001), skeletal muscle fibers (Ferrari et al., 1998), cardiomyocytes (Orlic et al., 2001), neuronal cells (Eglitis and Mezey, 1997), and renal tubular epithelial cells (Poulsom et al.,

2001). Bone marrow stromal cells, or mesenchymal stem cells (MSCs), produce mesodermal lineages such as osteoblasts, chondrocytes, adipocytes, myocytes, cardiomyocytes and thymic stroma (Beresford et al., 1992; Wakitani et al., 1995; Pittenger et al., 1999; Liechty et al., 2000; Poulsom et al., 2001). Human MSCs, transplanted into rats with cortical brain ischemia, migrate to the infarction site and differentiate into neuroendodermal cell types, which significantly ameliorate neurological defects (Zhao et al.,

2002). Similarly, in rats with traumatic brain injury, purified rat MSCs engraft into injury sites and express neuronal and astrocyte antigens and markedly reduce motor and neurological deficits (Mahmood et al., 2001). These differentiation pathways can be bidirectional as muscle (Jackson et al., 1999) and neuronal stem cells (Bjornson et al., 1999) can also form bone marrow, and fully differentiated cells can transdifferentiate into other adult cell types without undergoing cell division; for example, exocrine pancreatic cells can differentiate into hepatocytes in vitro (Shen et al.,

2000). Following induction of ischemia by coronary artery occlusion (Jackson et al., 1999) and myocardial infarction (Orlic et al.,

2001), bone marrow stem cells differentiate into cardiomyocytes, endothelial cells, and smooth muscle cells. Functional capability of the transdifferentiated cells in repair and regeneration of diseased tissue is demonstrated in fumarylacetoacetate hydrolase (FAH)-deficient mice, which resemble type 1 tyrosinemia in humans and are rescued from liver failure by transplantation of purified hematopoietic stem cells (HSCs) that differentiate into morphologically normal hepatocytes and express the FAH enzyme (Lagasse et al., 2000).

Studies of stem cell plasticity in the GI tract may provide insight into the mechanisms involved in the normal turnover of the GI mucosa and in GI tumorigenesis and disease. In lethally irradiated female mice that are rescued by a whole bone marrow transplant from male donors, the transplanted bone marrow cells were seen to engraft into the small intestine and colon and differentiate into intestinal subepithelial myofibroblast (ISEMF) cells located within the lamina propria underlying the GI epithelia. Indeed, 6 wk after transplantation, these bone marrow-derived ISEMFs were present as columns spanning from crypt base to luminal surface and thus potentially derived from a stem cell in the crypt base, proliferating upward to be shed at the luminal surface. The same study demonstrated bone marrow-derived ISEMFs in duodenal biopsies from human female patients who had developed graft-versus-host disease following bone marrow transplantation from a male donor. In both mouse and human, male donor cells were detected by ISH using a Y-chromosome-specific probe, and the newly differentiated ISMEF cell pheno-type was confirmed by positive immunohistochemical reactivity for a-smooth muscle actin (aSMA), and negativity for desmin, the mouse macrophage marker F4/80, and the hematopoietic precursor marker CD34 (Brittan et al., 2002). It is postulated that ISEMFs provide and maintain the intestinal epithelial stem cell niche via epithelial: mesenchymal cross talk and thus influence epithelial cell proliferation and ultimately determine intestinal epithelial cell fate (Powell et al., 1999).

After transplantation of a single purified hematopoietic bone marrow stem cell in the mouse, bone marrow-derived columnar epithelial cells were found in the lung, skin, esophageal lining, a single small intestinal villus, colonic crypt, and gastric pit of the stomach. Engraftment into the pericryptal myofibroblast sheath was not reported, and it is possible that ISEMFs derive from MSC populations within transplanted bone marrow since only a single HSC was transplanted in this study. This point can be addressed by studies of transplantation of defined stem cell populations (Krause et al., 2001). Similarly, in biopsies from human female patients who had received a sex-mismatched hematopoietic bone marrow transplant, 2-7% of epithelial cells in the skin and gastric cardia, and hepatocytes in the liver, expressed a Y-chromosome and therefore were derived from the transplanted donor hematopoietic bone marrow (Korbling et al., 2002). It is possible to engineer small intestinal tissue by grafting a cellular collagen sponge scaffold within the jejunum of dogs, although the regenerated tissue lacks muscularis layers necessary for peristalsis (Hori et al., 2001). Seeding of MSCs from bone marrow onto the collagen sponge scaffold prior to implantation induced initial development of an aSMA-positive muscle layer, although this regressed to a thin muscle layer 16 wk after transplant, and, therefore, it may be necessary to stimulate MSCs toward muscularis development (Hori et al., 2002).

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