A Mesenchymal-Like ZEB1+ Niche Harbors Dorsal Radial Glial Fibrillary Acidic Protein-Positive Stem Cells in the Spinal Cord

Abstract

In humans and rodents the adult spinal cord harbors neural stem cells located around the central canal. Their identity, precise location, and specific signaling are still ill-defined and controversial. We report here on a detailed analysis of this niche. Using microdissection and glial fibrillary acidic protein (GFAP)-green fluorescent protein (GFP) transgenic mice, we demonstrate that neural stem cells are mostly dorsally located GFAP(+) cells lying ependymally and subependymally that extend radial processes toward the pial surface. The niche also harbors doublecortin protein (Dcx)(+) Nkx6.1(+) neurons sending processes into the lumen. Cervical and lumbar spinal cord neural stem cells maintain expression of specific rostro-caudal Hox gene combinations and the niche shows high levels of signaling proteins (CD15, Jagged1, Hes1, differential screening-selected gene aberrative in neuroblastoma [DAN]). More surprisingly, the niche displays mesenchymal traits such as expression of epithelial-mesenchymal-transition zinc finger E-box-binding protein 1 (ZEB1) transcription factor and smooth muscle actin. We found ZEB1 to be essential for neural stem cell survival in vitro. Proliferation within the niche progressively ceases around 13 weeks when the spinal cord reaches its final size, suggesting an active role in postnatal development. In addition to hippocampus and subventricular zone niches, adult spinal cord constitutes a third central nervous system stem cell niche with specific signaling, cellular, and structural characteristics that could possibly be manipulated to alleviate spinal cord traumatic and degenerative diseases.

The late and dual origin of cerebrospinal fluid-contacting neurons in the mouse spinal cord

“…However, despite this evolutionary conservation, their function has not yet been fully elucidated. Gata2 + neurons of the central canal in newborn and young mice exhibit molecular and physiological characteristics of immature neurons, in agreement with previous observations (Stoeckel et al, 2003;Marichal et al, 2009;Sabourin et al, 2009;Orts-Del'Immagine et al, 2014Kútna et al, 2014).…”

“…In the spinal cord, the ependymal area surrounding the central canal comprises ependymocytes and several other cell types (Bruni, 1998;Meletis et al, 2008;Sabourin et al, 2009;Marichal et al, 2012). Cells located by the central canal, show a robust expression of the transcription factor Nkx6-1 (Fig.…”

“…The ependyma is composed of a layer of ciliated mural ependymocytes interspersed with tanycytes and CSF-contacting neurons (Bruni, 1998;Meletis et al, 2008;Sabourin et al, 2009;Marichal et al, 2012). Our genetic-tracing experiments with Gata3 Cre and Gata2 GFP selectively identified spinal CSF-cNs, which exhibit a unique morphology with a prominent dendritic process through the ependymal layer Vigh-Teichmann, 1971, 1998;Vigh et al, 1983) and express Pkd2l1 (Huang et al, 2006;Orts-Del'Immagine et al, 2014, 2016Djenoune et al, 2014).…”

The Spinal Cord Neural Stem Cell Niche

“…Notably, as observed for neurospheres that were derived from different brain regions (Armando et al 2007;Conti and Cattaneo 2010), neurospheres derived from different parts of the spinal cord have different growth and differentiation properties (Kulbatski and Tator 2009;Sabourin et al 2009). We showed that neurospheres that were derived from the cervical, thoracic and lumbar regions maintained their expression of specific and different rostro-caudal combinations of developmental homeogenes of the Hox family.…”

Regional differences of proliferation activity in the spinal cord ependyma of adult rats

“…To identify proliferating cells, we performed immunohistochemistry either for cell cycle S-phase marker 5-bromo-2-deoxyuridine (BrdU) or for the nuclear protein Ki-67, a marker expressed at all stages of the cell cycle. Both markers were previously used to detect cell division in parenchyma and CC region of the spinal cord in rodents [16,17].…”