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

Oct 31, 2003Leukemia

Bone marrow contains CXCR4-positive stem cells with early muscle, liver, and nerve cell traits

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Abstract

mRNA for various early markers of muscle, neural, and liver cells was detected in circulating blood mononuclear cells.

Tissue-committed stem cells may circulate in peripheral blood under steady-state conditions and increase during stress or injury.
These cells could be attracted to the bone marrow by a specific signaling molecule (SDF-1) that helps their retention.
Expression of early tissue-specific markers was found to increase in peripheral blood after mobilization by G-CSF.
Early tissue-specific cells were identified in normal bone marrow and were shown to express CXCR4 on their surface.
These cells can be significantly enriched (up to 60 times) when exposed to an SDF-1 gradient.
Increased expression of the SDF-1 signaling molecule was observed in damaged heart, kidney, and liver tissues.

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

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