N°30 I quarterly I july 2013 Live from the Labs | 9 w Biology Hematopoietic stem cells have been found to play an unexpected role—that of producing the appropriate cells in response to emergency situations. Triggering the Fate of Blood Stem Cells Not Committed Committed BY Clémentine Wallace Hematopoietic stem cells (HSCs), located in the bone marrow, are characterized by their ability to self- renew and continuously generate all types of blood cells, such as white blood cells, red blood cells, or platelets. Until recently, HSCs were believed to give rise to each cell type randomly, independently of any external influence. In 2009, a French- German research team1 led by Michael Sieweke showed that, on the contrary, stem cells are sensitive to their environment. This year, the same team demonstrated that in case of emergencies such as infections, HSCs react by orienting their production, manufacturing the most appropriate cells to face the danger.2 The scientists discovered that HSCs are sensitive to the “Macrophage Colony- Stimulating Factor” (M-CSF), a molecule produced in large quantities during infections. M-CSF activates a gene called PU.1 inside HSCs, thus boosting the production of white blood cells required to fight off infections. The researchers first isolated individual HSCs from mouse bone marrow using flow cytometry and analyzed them with state-ofthe art single-cell technologies. “This was a real challenge: stem cells are extremely rare and difficult to distinguish from their descendants,” explains Sieweke. To overcome this problem, the team used a fluorescent marker indicating when the PU.1 gene in HSCs was “switched on.” Following each cell by videomicroscopy in vitro showed that cells lit up rapidly in response to M-CSF addition to the tissue culture. Using microfluidic chips, the scientists analyzed the genetic expression of each individual HSC after M-CSF exposure. The genes activated were indeed those involved in the production of white blood cells. The researchers showed that the process also occurred in vivo by transplanting marked-HSCs in mice. An injection of M-CSF was indeed immediately followed by PU.1 activation. Sieweke suggests this property could one day be used to strengthen the immunity of bone marrow transplant recipients, who are particularly vulnerable to infections. “It may be possible to boost patients’ pool of white blood cells by injecting M-CSF before an infection actually occurs,” says Sieweke. “What is particularly interesting is that M-CSF stimulates the production of leucocytes without inducing that of lymphocytes, which would be responsible for graft-versus-host disease.” 01. Centre d’immunologie de Marseille-Luminy (CIML) (CNRS / Inserm / Aix-Marseille Université) and Max-Delbrück- Centrum für Molekulare Medizin, Berlin-Buch (Germany). 02. N. Mossadegh-Keller et al., “M-CSF instructs myeloid lineage fate in single haematopoietic stem cells,” Nature, 2013. 497: 239-43. Contact information: CIML , Marseille. Michael Sieweke > sieweke@ciml.univ-mrs.fr q Blood stem cells, identified by their nucleus (blue) and controlled for their protein content (green), express PU.1 (red) only in the presence of M-CSF (committed vs not committed). © C.Bernard Contact information: LPP, Paris. Judit Gervain > judit.gervain@parisdescartes.fr © Michael Sieweke ’s laboratory , CIML Paris Marseille babies, when listening to speech, can exploit non-grammatical cues that monolingual babies do not need to pay attention to,” concludes Gervain. 01. J. Gervain and J.F. Werker, “Prosody cues word order in 7-month-old bilingual infants,” Nat Commun., 2013. 4:1490. doi: 10.1038/ncomms2430. 02. Laboratoire psychologie de la perception (CNRS / Université Paris Descartes).
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