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  • Here we report that Dll counteracts the proliferation of mur

    2018-11-12

    Here we report that Dll4 counteracts the proliferation of murine HPCs such as Lin−Sca+c-Kit+ (LSK) cells, by keeping a higher fraction of cells in the G0 state. This event was correlated with a downmodulation of some key Okadaic acid cost genes transcription such as D-CYCLINS. Furthermore, Dll4 limits the loss of the short-term reconstitutive potential, as assessed by in vivo reconstitution assay, correlated with up-regulation of well-known self-renewal genes transcription such as BMI1, HOXB4, GATA2 and C-MYC as well as PUMILIO1 and -2, two RNA-binding proteins previously identified as regulators involved in stem cell proliferation in invertebrates. Altogether, these data reinforce the major role of the Notch ligand Dll4 in the vascular niche as a new player in HPCs maintenance.
    Materials and methods
    Results
    Discussion In accordance with our previous work performed on human CD34+ CD38low cord blood cells (Lauret et al., 2004), mbDll4 reduces murine bone marrow HPCs cell expansion correlated with the retention of their primitive potential in vitro. The present study further reveals that the reduced cell proliferation was mainly due to the maintenance of a higher proportion of HPCs in the G0 state. It also shows that cell culture on mbDll4-expressing stroma limits the loss of their short term repopulating capacity in vivo, and finally leads to the identification of the gene signature of HPCs in response to Notch/Dll4 signalling.
    Conclusion Our observations strongly indicate that the vascular Notch/Dll4 ligand exerts a dormant activity on HPCs, distinct from other Notch ligands, and displays clear-cut positive effects on the maintenance of the primitive functions of murine HPCs in culture. Furthermore, the link between Pumilio and Dll4/Notch pathway in the function of HPCs is a new understanding step in the mechanism of the Notch signalling pathway. These newly identified factors, PUM1 and PUM2, could be implicated in the expansion and maintenance of HPCs.
    Funding sources Fabio Michelet and Aurore Hattabi are fellows from the French Research Ministry. This work was supported by grants from INSERM, Institut Gustave Roussy (Contrat de Recherche Clinique, no. 2000.10 and CRI-SPS-2003-02), ATC Cellules Souches, LNC, and ARC. Our group is supported by the Centre National de la Recherche Scientifique (CNRS), and the Institut National de la Santé et de la Recherche Médicale (INSERM).
    Authorship and disclosures
    Acknowledgments
    Introduction Alzheimer\'s disease (AD) is the most common cause of neurodegenerative dementia in elderly people; currently, the disease affects more than 36 million people worldwide. AD is characterized by slowly progressive recent memory deficits, cognitive impairment, and personality changes associated with neuronal loss (Blennow et al., 2006). The main risk factor of sporadic AD is aging; prevalence after 65years of age is 5%, increasing to about 30% of people aged over 85years old. As a result of the prolonged lifespans in our aging society, the number of patients is expected to continue to increase in the future (Ferri et al., 2005). At the moment, only symptomatic therapies for this disease are available, and the development of a disease-modifying therapy is a required (Carter et al., 2010). The two major pathological hallmarks of AD are extracellular senile plaques and intraneuronal neurofibrillary tangles. Senile plaques mainly consist of β amyloid peptide (Aβ), especially the Aβ1–42 isoform. Based on the genetic findings from familial AD studies, Aβ is assumed to be the primary inducer of AD pathology (Hardy and Selkoe, 2002; Tanzi and Bertram, 2005). Transgenic mouse lines that accumulate Aβ in their brains are used as experimental models to identify a therapeutic approach for AD. Previous studies have shown that vaccination reduced the brain Aβ deposits and improved cognitive functions in these model animals (Janus et al., 2000; Morgan et al., 2000; Schenk et al., 1999). Nevertheless, in the human clinical trials, vaccination therapy has failed to improve cognitive function so far (Robinson et al., 2004). Furthermore, several adverse events such as meningo-encephalitis (Nicoll et al., 2003), vasogenic edema (Salloway et al., 2009), and micro hemorrhage (Boche et al., 2008) occurred in some of the treated patients.