Embryonic stem cell (ESC) is an attractive and promising source in regenerative medicine. However, current technologies for ESC differentiation do not ensure complete or synchronized conversion of ESCs into a specific functional tissue type for therapeutic purposes. Thus, un-differentiated ESCs, though few, may be still contained in the therapeutic ESC derivatives. It is yet to be determined whether un-differentiated ESCs can survive in adult organs/tissues for a long term in vivo. Previous studies have been aimed to isolate ESC-like cells from somatic tissues or organs 1, 2. Embryonic remnants were thought to be “lost” during organogenesis and remain dormant in adult tissues/organs. Bone marrow (BM) has been identified as a major source containing hematopoietic stem cells (HSCs) as well as some non-hematopoietic primitive stem cells, which include mesenchymal stem cells 3, multipotent adult progenitor cells 4, marrow-isolated adult multilineage inducible cells 5, and very small embryonic-like stem cells 6. Some of these non-hematopoietic bone-marrow-derived stem cells have been shown to have features in common with ESCs, as indicated by the expression of the ESC marker gene Oct4. The multipotent adult progenitor cells (so called “MAPCs”) were once shown to differentiate into each of the three germ layer cells. However, the claim regarding the existence of ESC-like cells in adult tissues/organs such as BM remains controversial largely due to the difficulty in isolating these extremely rare cells.

Using two-photon microscopy, we were able to directly observe the GFP+ cells and their relationship with the endosteal region in the BM. Oct4+-GFP+ cells stayed alive in the BM for at least 100 days after transplantation (Figure 1B). Although the time span of capturing the GFP+ cells was equally long in both irradiated and un-irradiated groups, more GFP+ cells could be observed in the irradiated group and the frequency of observation of GFP+ cells was higher. The irradiated microenvironment might be more conducive to the integration of grafted ESCs since irradiation could compromise or mobilize HSCs and promote blood cells to vacate from the BM niches of the recipients to make “space” for the donor cells. In addition, the roles of some unique signals from irradiated hosts in the maintenance of ESCs cannot be excluded. These may also explain why we could only recover ESC-like lines from the irradiated BM, as described below. We also found GFP+ cells in the BM of the bone opposite from the injection site (Figure 1C). Two-photon microscopy and immunofluorescence results showed that most GFP+ cells were randomly distributed in the injection site without physical proximity to the endosteal regions (Figure 1D). These observations suggest that the microenvironmental elements for ESCs, if present in the BM, may be different from the niche of HSCs.

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