Analysis of developmental plasticity of bone marrow-derived cells (BMDCs) is complicated by the possibility of cell-cell fusion. Here we demonstrate that epithelial cells can develop from BMDCs without cell-cell fusion. We use the Cre/lox system together with beta-galactosidase and enhanced green fluorescent protein expression in transgenic mice to identify epithelial cells in the lung, liver, and skin that develop from BMDCs without cell fusion.

Stem cell plasticity refers to the ability of adult stem cells to acquire mature phenotypes that are different from their tissue of origin. Adult bone marrow cells (BMCs) include two populations of bone marrow stem cells (BMCs): hematopoietic stem cells (HSCs), which give rise to all mature lineages of blood, and mesenchymal stem cells (MSCs), which can differentiate into bone, cartilage, and fat. In this article, we review the literature that lends credibility to the theory that highly plastic BMCs have a role in maintenance and repair of nonhematopoietic tissue. We discuss the possible mechanisms by which this may occur. Also reviewed is the possibility that adult BMCs can change their gene expression profile after fusion with a mature cell, which has brought into question whether this stem cell plasticity is real.

Recent findings suggest that bone marrow-derived cells (BMDC) may contribute to tissue maintenance throughout the body. However, it is not yet known whether marrow-derived epithelial cells are capable of undergoing proliferation. Our laboratory has shown that BMDC engraft as keratinocytes in the skin at low levels (< 1%) in the absence of injury. Here we show that skin damage affects the degree of engraftment of BMDC as keratinocytes and that the keratinocytes are actively cycling. Female mice reconstituted with sex-mismatched BM were wounded by punch biopsy and incision. At the wound site, engraftment of BMDC as epidermal cells increased within 1 day, and continued to increase to approximately 4% by 3 weeks after injury. Using a Cre-lox system, fusion of BMDC with epithelial cells was ruled out. BMDC-derived epithelial cells at the wound edges expressed Ki67, a marker for actively cycling cells, and this proliferation correlated with an increase in the number of donor-derived cells within the wound. Donorderived cytokeratin 5-expressing cells were rare, suggesting that BMDC do not engraft as epidermal stem cells, and the level of engraftment peaked and then decreased over time, further suggesting that BMDC may assist in early wound healing by engrafting as transit-amplifying cells, which then differentiate into keratinocytes. We have shown that, in the absence of injury, bone marrow-derived cells (BMDC) engraft at low levels as epithelial cells in the liver, lung, GI tract, and skin. It is not yet clear whether this phenomenon is due to transdifferentiation of a hematopoietic stem cell, or whether the marrow contains pluripotent pre-hematopoietic cells thathave not yet initiated a gene expression pattern that commits them to either a hematopoietic or an epithelial fate (reviewed in 1 ). According to recent studies, BMDC show an increased contribution to tissues under pathological conditions. Following acute myocardial infarction, BMDC engraft as multiple cell types that promote survival/regeneration of heart tissue.2,3 A more pronounced effect is seen in a mouse model of tyrosinemia, where fusion of BMDC with diseased cells results in the formation of functional hepatocytes and restores liver function. 4 These findings led us to investigate whether cutaneous injury leads to increased engraftment of BMDC as epidermal cells.To allow for tracking of the BMDC, we reconstituted lethally irradiated mice with sex-mismatched BM. Following engraftment, we wounded the skin with full-thickness punch biopsies and incisional wounds, each of which heals by secondary intention. Analysis of the healing skin at different times showed that engraftment of BMDC as epidermal cells in the wounded area was significantly greater than in unwounded skin over the same time interval. The marrow-derived epithelial cells just beyond the wound edges were undergoing proliferation. Fusion was ruled out using the loxP-Cre system. Based on the pattern of engraftment over time, a conceptual model of this engraftment is proposed. Materials and Met...

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