Abstract
During development, the nervous system with its highly specialized cell types forms from a pool of relatively uniform stem cells. This orchestrated process requires tight regulation. The extracellular matrix (ECM) is a complex network rich in signaling molecules, and therefore, of interest in this context. Distinct carbohydrate structures, bound to ECM molecules like Tenascin C (TNC), are associated with neural stem/progenitor cells. We have analyzed the expression patterns of the LewisX (LeX) trisaccharide motif and of the sulfation-dependent DSD-1 chondroitin sulfate glycosaminoglycan epitope in human cerebral organoids, a 3D model for early central nervous system (CNS) development, immunohistochemically. In early organoids we observed distinct expression patterns of the glycoepitopes, associated with rosette-like structures that resemble the neural tube in vitro: Terminal LeX motifs, recognized by the monoclonal antibody (mAb) 487LeX, were enriched in the lumen and at the outer border of neural rosettes. In contrast, internal LeX motif repeats detected with mAb 5750LeX were concentrated near the lumen. The DSD-1 epitope, labeled with mAb 473HD, was detectable at rosette borders and in adjacent cells. The epitope expression was maintained in older organoids but appeared more diffuse. The differential glycoepitope expression suggests a specific function in the developing human CNS.
Highlights
The development of the nervous system starts with the induction of the neuroectoderm, followed by the formation of the neural tube by cells with a radial morphology
After neural induction of the human Embryoid Bodies according to the protocol of Lancaster et al [38], the morphology of the cell aggregates changed dramatically
Small protrusions formed on the surface of the early cerebral organoid after 18 days in vitro (DIV) (Figure 1A)
Summary
The development of the nervous system starts with the induction of the neuroectoderm, followed by the formation of the neural tube by cells with a radial morphology. Emanating from the single-layered neural tube, differentiation and migration processes lead to the formation of complex layers, as seen in the neocortex and other neural tissues [1,2]. All these events require tight regulation of processes, such as proliferation, migration and differentiation. In combination with intrinsic programs of the cells, extracellular signals are indispensable for proper nervous system development. In this context, the extracellular matrix (ECM) is of utmost interest [3]. Glycosylation, namely the attachment of carbohydrates to ECM molecules, is one type of modification
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