Abstract
Very small embryonic-like (VSEL) cells have been described as putatively pluripotent stem cells present in murine bone marrow and human umbilical cord blood (hUCB) and as such are of high potential interest for regenerative medicine. However, there remain some questions concerning the precise identity and properties of VSEL cells, particularly those derived from hUCB. For this reason, we have carried out an extensive characterisation of purified populations of VSEL cells from a large number of UCB samples. Consistent with a previous report, we find that VSEL cells are CXCR4+, have a high density, are indeed significantly smaller than HSC and have an extremely high nuclear/cytoplasmic ratio. Their nucleoplasm is unstructured and stains strongly with Hoechst 33342. A comprehensive FACS screen for surface markers characteristic of embryonic, mesenchymal, neuronal or hematopoietic stem cells revealed negligible expression on VSEL cells. These cells failed to expand in vitro under a wide range of culture conditions known to support embryonic or adult stem cell types and a microarray analysis revealed the transcriptional profile of VSEL cells to be clearly distinct both from well-defined populations of pluripotent and adult stem cells and from the mature hematopoietic lineages. Finally, we detected an aneuploid karyotype in the majority of purified VSEL cells by fluorescence in situ hybridisation. These data support neither an embryonic nor an adult stem cell like phenotype, suggesting rather that hUCB VSEL cells are an aberrant and inactive population that is not comparable to murine VSEL cells.
Highlights
Over the last ten years, there have been various reports of the isolation of putatively pluripotent cells from bone marrow, umbilical cord blood and other tissues [1,2,3,4]
The immunophenotype of CD452Lin2 human umbilical cord blood (hUCB) cells Human umbilical cord blood derived very small embryonic-like (VSEL) cells have been described to be CD452Lin2 and to carry one or more of the cell surface markers CXCR4, CD133, CD34 and SSEA-4. None of these markers is unique for VSEL cells, as they are expressed on hematopoietic stem and progenitor cells (CD34, CD133), leucocytes (CXCR4) or erythroid cells (SSEA-4)
Aiming to define the VSEL cell phenotype more thoroughly, we selected a number of established markers for embryonic, mesenchymal, hematopoietic and neuronal stem cells, and analysed their abundance and distribution on the population of living nucleated CD452Lin2 cells, of which the VSEL population is a part
Summary
Over the last ten years, there have been various reports of the isolation of putatively pluripotent cells from bone marrow, umbilical cord blood and other tissues [1,2,3,4]. The discovery of very small embryonic-like (VSEL) stem cells in adult bone marrow and umbilical cord blood promised to shed light on this controversy, since here for the first time was a highly versatile and putatively pluripotent cell type that could be isolated directly from primary tissue and investigated without the need for intervening culture [8,9]. Murine VSEL cells have been described as a rare population of small cells which over express pluripotency genes including Oct, Nanog and SOX2 at both the mRNA and protein levels, and maintain a demethylated Oct promotor. They have euchromatic nuclei and are reportedly able to adopt the phenotype of tissues from all three germ layers upon differentiation in vitro. It has been suggested that VSEL cells could play a role in regeneration and tissue repair, both their true physiological function and their origin remain uncertain
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