###### Abstract
Particular relevance goes to Neural Stem Cells (NSCs), where non-coding genes have been found to be involved in important functions [11; 13; 14; 15; 16] such as stemness maintenance and differentiation [11]. Furthermore, small non-coding RNAs have been implicated in these processes, and these include _miR-342-5p_, a downstream effector of Notch signaling which regulates the differentiation of NSCs and intermediate neural progenitors into astrocytes [13]. A strong implication is also present for lncRNAs as in the adult brain and in embryonic stem cells several lncRNAs were found to be specifically deregulated, suggesting a potential role in central nervous system development [17]. Other regulators include _PSORS1C3_, a lncRNA overlapped with _OCT4_ which is a novel fine-tuner of its expression in non-pluripotent cells [14], and _TUNA_, detected at the promoters of _Nanog, Sox2_, and _Fgf4_, required for pluripotency and neural differentiation [18]. Furthermore, we also reported in our previous work the implications of a specific panel of lncRNAs, which are dysregulated during murine NSCs differentiation and exert their action through the interaction with the RNA binding protein _ELAVL1 (HuR)_[11]. In recent years, growing efforts in the field of biomedical research were directed towards finding new strategies to mimic the physiological environment ex vivo, in order to better simulate the native stemness potential of the cells, recreating a niche-like environment [19; 20; 21; 22; 23]. Here, we focused on the potential of the scaffold called \"Nichoid\" [24; 25], engineered in the form of a 3D micro-grid in order to mimic the 3D microscopic architecture of a stem cells niche. The Nichoid already demonstrated able to maintain the stemness capacity of primary rat mesenchymal stem cells (MSCs), human bone marrow-derived MSCs, mouse ES cells [26; 27; 28; 29] and NPCs [30; 31]. In this context, we have already investigated how the 3D spatial structure of the Nichoid scaffold can influence gene expression through the alteration of mechanotransduction-related processes, subsequently influencing the stemness and therapeutic potentials of NPCs [30; 31; 32]. Specifically, the deregulated coding genes and subsequent pathways analysis showed that the Nichoid causes alterations in genes starting at a membrane level, through an impact on signaling transduction and cellular metabolism, which ultimately leads to altered nuclear activity and thus changes in cellular functions. These pathways include focal adhesions, integrins, cadherins, and Rho activation, fundamental in bundling of actin filaments and promoting contractility. Furthermore, significant pathways as MAPK cascade, PI3K-Akt, AMPK, Wnt, and RAP1 signaling, implicated in proliferation, cell motility, and migration result deregulated in NPCs grown inside the Nichoid respect to the control condition, all leading to a final coral alteration in coding genes expression [32]. Little is known on the role of non-coding genes in alterations due to a 3D micro-scaffold cells expansion. In 2017, a group of researchers investigated how the stiffness of the matrix regulates the transcriptome profile of human aortic and coronary vascular smooth muscle cells (VSMCs) and identified potential key lncRNAs regulators [33]. Furthermore, the same authors reported that _MALATI_ is a positive regulator of VSMCs proliferation and migration in response to ECM stiffness [31]. We thus investigated the transcriptional deregulation of non-coding RNAs present in NPCs grown in standard floating conditions or inside the Nichoid through RNA-Sequencing (RNA-Seq) approach [32], performing a computational dissection and highlighting their co-interactions with coding genes and potential pathways implications, with a focus on mechanotransduction and stemness.