Stem cells know it’s their time to circulate

by on February 25, 2008 · 2 comments

in Journal club, niche

Blogging on Peer-Reviewed ResearchIt is known that hematopoietic stem cells (HSCs) circulate in blood under physiological conditions (1), and a possible role of circulating stem cells for immunosurveillence has been recently suggested (2). However, it is not known whether this physiological stem cell circulation happens in a constant rate, or the rate varies over time.

A group led by Paul Frenette in Mount Sinai Medical Center (New York, USA) accidently discovered that by exposing mice to light, they were able to increase stem cells under G-CSF (granulocyte colony-stimulating factor) administration, which has been used as a stem cell mobilization agent in clinics. Since the photic cues are processed in the central nervous system, and given a previous implication of the nervous system in controlling stem cell number and functions (3, 4), the group investigated the circadian patterns and the mechanisms behind HSCs release into circulation in homeostasis.

They showed that HSCs circulate in blood in a circadian manner by looking at colony-forming unit, LSK (Lin-/c-Kit+/Sca-1+) cell number and limiting dilution-competitive repopulation assay to show that there are 2~3 times more HSCs after 5 hours of light exposure (peak) than 5 hours after darkness (trough). They went further to show that the expression level of both CXCL12 (SDF-1) protein and mRNA in bone marrow oscillates and this oscillation is regulated by adrenergic beta3 receptors as shown by a series of pharmacological experiments. They attempted to elucidate mechanisms behind this process further by showing that stimulation of beta3 receptor but not other adrenergic receptors leads to increased expression of Sp transcription factors which may in turn regulate the expression of CXCL12.

Although they showed that Bmal1-/- mice, which have dysfunctional circadian rhythms, exhibit abolition of HSC oscillation in blood, they failed to connect the involvement of known circadian rhythm genes in regulating CXCL12 oscillation. In addition, beta3 receptors are not expressed in osteoblasts, suggesting that stromal cells other than osteoblasts may regulate oscillation of HSCs mobilization. There are existing mouse models for selectively manipulating osteoblast number (5,6,7), but the current study is only limited to in vitro observation to address the nature of niche cells regulating HSCs oscillation.

Nevertheless, the study is novel and a clever extension from previous observations combining physiological circulation and sympathetic nervous system regulation of HSCs. The clinical implication of this study will be more convincing if it is shown that G-CSF or PTH treatment to increase HSC collection from the periphery will be enhanced if harvested at a certain time during the day.

Nature AOP 6 Feb. 2008; doi:10.1038/nature066852008

references:

1. Wright DE, et al. Science. 2001 Nov 30;294(5548):1933-6.
2. Massberg S, et al.Cell. 2007 Nov 30;131(5):994-1008.
3. Katayama Y, et al. Cell. 2006 Jan 27;124(2):407-21.
4. Spiegel A, et al. Nat Immunol. 2007 Oct;8(10):1123-31.
5. Zhang J, et al. Nature. 2003 Oct 23;425(6960):836-41.
6. Calvi LM, et al. Nature. 2003 Oct 23;425(6960):841-6.
7. Visnjic D, et al. Blood. 2004 May 1;103(9):3258-64.

{ 2 comments… read them below or add one }

virgin health banks May 12, 2008 at 1:22 pm

Its good to see somebody else spreading the word about stem cells. I wasnt aware that this kind of research was going on. The possibilities

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JWS May 12, 2008 at 5:12 pm

Thank you for the comment. It is not certain yet whether this particular finding is going to impact collection of a large number of stem cells from circulating blood (just 2~3 fold). However, it is also important to remember that simply increasing number of stem cells (e.g. ex vivo methods) is not going to help much either. The key is to increase the number and at the same time to maintain functionalities of stem cells. That is why cord blood bank or any method that employs stem cells at physiological levels is going to be important.

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