Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):E5954-E5962. doi: 10.1073/pnas.1803297115. Epub 2018 Jun 11.
In the adult mouse spinal cord, the ependymal cell population that surrounds the central canal is thought to be a promising source of quiescent stem cells to treat spinal cord injury. Relatively little is known about the cellular origin of ependymal cells during spinal cord development, or the molecular mechanisms that regulate ependymal cells during adult homeostasis. Using genetic lineage tracing based on the Wnt target gene , we have characterized Wnt-responsive cells during spinal cord development. Our results revealed that Wnt-responsive progenitor cells are restricted to the dorsal midline throughout spinal cord development, which gives rise to dorsal ependymal cells in a spatially restricted pattern. This is contrary to previous reports that suggested an exclusively ventral origin of ependymal cells, suggesting that ependymal cells may retain positional identities in relation to their neural progenitors. Our results further demonstrated that in the postnatal and adult spinal cord, all ependymal cells express the Wnt/β-catenin signaling target gene , as well as Wnt ligands. Genetic elimination of β-catenin or inhibition of Wnt secretion in Axin2-expressing ependymal cells in vivo both resulted in impaired proliferation, indicating that Wnt/β-catenin signaling promotes ependymal cell proliferation. These results demonstrate the continued importance of Wnt/β-catenin signaling for both ependymal cell formation and regulation. By uncovering the molecular signals underlying the formation and regulation of spinal cord ependymal cells, our findings thus enable further targeting and manipulation of this promising source of quiescent stem cells for therapeutic interventions.
在成年小鼠脊髓中，环绕中央管的室管膜细胞群体被认为是治疗脊髓损伤的静止干细胞的有前途的来源。相对而言，人们对脊髓发育过程中室管膜细胞的细胞起源，或调节成年期室管膜细胞稳态的分子机制知之甚少。我们利用基于 Wnt 靶基因的遗传谱系追踪，对脊髓发育过程中的 Wnt 反应细胞进行了特征描述。我们的结果表明，Wnt 反应性祖细胞在整个脊髓发育过程中局限于背中线，在空间上局限地产生背侧室管膜细胞。这与以前的报告相反，以前的报告表明室管膜细胞仅起源于腹侧，这表明室管膜细胞可能与其神经祖细胞保持位置身份。我们的结果还表明，在出生后和成年的脊髓中，所有的室管膜细胞都表达 Wnt/β-catenin 信号靶基因，以及 Wnt 配体。体内 Axin2 表达的室管膜细胞中β-catenin 的遗传缺失或 Wnt 分泌的抑制均导致增殖受损，表明 Wnt/β-catenin 信号促进室管膜细胞增殖。这些结果表明 Wnt/β-catenin 信号对室管膜细胞的形成和调节仍然很重要。通过揭示脊髓室管膜细胞形成和调节的分子信号，我们的发现从而能够进一步针对和操纵这种有前途的静止干细胞来源，用于治疗干预。
