I- Regeneration of the spinal cord and adult stem cells

Anamniotes such as Salamaders or Zebrafishes can regenerate their spinal cord after lesions  by producing new cells, including motoneurons, thanks to ependymal cells situated around the spinal cord central canal which are endowed with stem cell properties (Figure 1).

 

JPH Fig1 site

 

 

Figure 1: The adult spinal cord ependymal region in different species (from Becker C, Becker T, Hugnot JP, Progress in Neurobiology 2018).

 

 

 

 

 

 

Mammals are not able to regenerate their spinal cord to such an extend however they maintain a pool of ependymal cells presenting immature features and similarities with anamniotes stem cells. In particular, rodent ependymal cells cells are highly reactive to spinal cord lesions by increasing their proliferation and by differentiating into new glia cells. This ependymal region comprises several types of cells including stem and non stem cells. Our goal is to explore this adult stem cell niche at the cellular and molecular levels, both in mouse and human,  to understand the signalling and genes operating to maintain this stem cell pool. We are also interested in the detailed molecular mechanisms influencing the different adult stem cell fates (quiescence, proliferation, glial vs neuronal  differentiation).

 

Fundings

AFM, IRB, IRME, ANR ERANET, INSERM

 

II- Cancer stem cells and gliomas

Gliomas are the most frequent brain tumors affecting around 5000 new patients each year in France. These tumors are thought to be derived from adult brain progenitor or stem cells. Glioblastomas are the most aggressive and frequent form of gliomas. Glioblastomas frequently contain a pool of cancer stem cells which are highly resistant to treatments and which may be responsible to glioma relapse. Beside glioblastomas, there exists diffuse low grade gliomas which may ultimately increase in malignancy.

Several goals are pursued in the lab:

                1- We are using diffuse low grade glioma resections freshly obtained from the hospital (Pr H Duffau) to understand the origin and the diversity of  the tumoral cells. We are also particularly interested in the genes and the signalling involved in the maintenance of these diffuse low grade glioma cells and to understand their progression into high grade gliomas. We have developed original culture models of these tumoral for these purposes (Figure 2).

 

 JPH fig 2 site

 

Figure 2: Primary culture of diffuse low grade glioma cells

 

 

 

 

 

 

 

 

 

 

 

                2- We have found that a high level of Notch signalling (Guichet, Stem Cells, 2015) or introduction of bHLH neurogenic genes (Guichet, Glia, 2013) can stop the proliferation of glioblastoma stem cells and drastically modify their phenotype (Guelfi,  Stem Cells Int, 2016) (Figure 3). We are currently exploring how the Notch signalling and other pathways influence the proliferation and differentiation of glioblastoma stem cells.

JPH Fig 3 site

 

 

Figure 3: Reversible  modifications of glioblastoma stem cell phenotype and proliferation by high Notch signaling (from Guichet, Stem cells, 2015)

 

 

 

 

 

 

Fundings

Gefluc, GSO-INCA, ARC, La ligue contre le cancer

 

Major publications

Guichet PO et al., Stem Cells, 33(1):21-34, 2015
Rème T et al., PLoS One, 8(6):e66574, 2013
Guichet PO et al., Glia, 61(2):225-39, 2013
Hugnot JP et al., Frontier in Bioscience, 16:1044-59, 2011 
Mamaeva D et al., BMC Neurosci, 12:99, 2011
Sabourin JC et al., Stem Cells, 27(11):2722-33, 2009

 

Collaborations

  • CEA Saclay

CEA Saclay, Imaging of brain tumors

 

 

 

Contact

Hugnot Jean-Philippe