Stem cell plasticity revisited: CXCR4-positive cells expressing mRNA for early muscle, liver and neural cells 'hide out' in the bone marrow

被引:269
作者
Ratajczak, MZ
Kucia, M
Reca, R
Majka, M
Janowska-Wieczorek, A
Ratajczak, J
机构
[1] Univ Louisville, James Graham Brown Canc Ctr, Stem Cell Biol Program, Louisville, KY 40202 USA
[2] Univ Louisville, Dept Med, Louisville, KY 40202 USA
[3] Jagiellonian Univ, Coll Med, European Stem Cell Therapeut Excellence Ctr, Krakow, Poland
[4] Univ Alberta, Edmonton, AB, Canada
[5] Canadian Blood Serv, Edmonton, AB, Canada
关键词
CXCR4; SDF-1; stem cell plasticity; stem cell mobilization; stem cell homing;
D O I
10.1038/sj.leu.2403184
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
It has been suggested that bone marrow (BM)-derived hematopoietic stem cells transdifferentiate into tissue-specific stem cells (the so-called phenomenon of stem cell plasticity), but the possibility of committed tissue-specific stem cells pre-existing in BM has not been given sufficient consideration. We hypothesized that (i) tissue-committed stem cells circulate at a low level in the peripheral blood (PB) under normal steady-state conditions, maintaining a pool of stem cells in peripheral tissues, and their levels increase in PB during stress/tissue injury, and (ii) they could be chemoattracted to the BM where they find a supportive environment and that the SDF-1-CXCR4 axis plays a prominent role in the homing/retention of these cells to BM niches. We performed all experiments using freshly isolated cells to exclude the potential for 'transdifferentiation' of hematopoietic stem or mesenchymal cells associated with in vitro culture systems. We detected mRNA for various early markers for muscle (Myf-5, Myo-D), neural (GFAP, nestin) and liver (CK19, fetoprotein) cells in circulating (adherent cell-depleted) PB mononuclear cells (MNC) and increased levels of expression of these markers in PB after mobilization by G-CSF (as measured using real-time RT-PCR). Furthermore, SDF-1 chemotaxis combined with real-time RT-PCR analysis revealed that (i) these early tissue-specific cells reside in normal murine BM, (ii) express CXCR4 on their surface and (iii) can be enriched (up to 60 x) after chemotaxis to an SDF-1 gradient. These cells were also highly enriched within purified populations of murine Sca-1(+) BM MNC as well as of human CD34(+)-, AC133(+)- and CXCR4-positive cells. We also found that the expression of mRNA for SDF-1 is upregulated in damaged heart, kidney and liver. Hence our data provide a new perspective on BM not only as a home for hematopoietic stem cells but also a 'hideout' for already differentiated CXCR4-positive tissue-committed stem/progenitor cells that follow an SDF-1 gradient, could be mobilized into PB, and subsequently take part in organ/tissue regeneration.
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页码:29 / 40
页数:12
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