Several recent studies in animals as well as humans support the notion that bone marrow (BM)-derived cells participate in brain regeneration. However, the identity of the specific cell type responsible for regeneration remains unknown. Recent work from our laboratory revealed that BM contains a highly mobile population of CXCR4+ cells that express mRNA for various markers of early tissue-committed stem cells (TCSC) and which are distinct from hematopoietic stem cells (HSC) (

Leukemia 2004:18;29–40
). In this study we investigated whether BM also contains a mobile pool of TCSC destined to differentiate into neural cells. The TCSC were isolated from bone marrow by employing chemotactic gradient to SDF-1 or by FACS sorting and subsequently evaluated for a presence of early neural markers by i) real time RT-PCR analysis (nestin, GFAP), ii) immunohistochemical staining (nestin, beta-III tubulin), and iii) by employing functional in vitro assays to study ability of these purified cells to form neurospheres. Our data demonstrate that TCSC for neural cells (i) are present in significant amounts in BM harvested from young (1–2 month-old) while being barely detectable in older (1-year-old) mice; ii) reside in populations of murine BM-derived non-adherent non-hematopoietic Sca-1+ CD45− cells and in population of human CXCR4+ CD34+ AC133+ CD45− BMMNC, iii) are mobilized from BM into peripheral blood (PB) during pharmacological mobilization or 24 hours after Bengal-rose induced stroke in mice; iv) SDF-1 is highly upregulated in damaged brain tissue, and v) TCSC are chemoattracted for potential brain regeneration in SDF-1-CXCR4, dependent manner. Thus, we conclude that bone marrow is a potential source of TCSC for brain repair and since purified CD45+ HSC neither express neuronal markers nor differentiate in vitro into neurospheres, we provide for a first time evidence that neural TCSC residing in bone marrow but not “plastic” HSC account for neural differentiation of BM-derived cells. Furthermore, our observation that the number of marrow derived mobile/circulating neural TCSC is the highest in BM of young animals and decreases with age provides a novel insight into aging and may explain why the brain regeneration process becomes less effective in older individuals. Finally, these observations provide rationale for further studies aimed at optimizing therapeutic brain regeneration by BM-derived neural TCSC.

Topics:
bone marrow, cerebrovascular accident, cxcr4 receptors, ischemic stroke, stem cells, cd45 antigens, stromal cell-derived factor 1, cd34 antigens, leukemia, repair of brain

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2005, The American Society of Hematology
2004
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