Take the shortcut – direct conversion of somatic cells into induced neural stem cells and their biomedical applications

Abstract

Second-generation reprogramming of somatic cells directly into the cell type of interest avoids induction of pluripotency and subsequent cumbersome differentiation procedures. Several recent studies have reported direct conversion of human somatic cells into stably proliferating induced neural stem cells (iNSCs). Importantly, iNSCs are easier, faster, and more cost-efficient to generate than induced pluripotent stem cells (iPSCs), and also have a higher level of clinical safety. Stably, self-renewing iNSCs can be derived from different cellular sources, such as skin fibroblasts and peripheral blood mononuclear cells, and readily differentiate into neuronal and glial lineages that are indistinguishable from their iPSC-derived counterparts or from NSCs isolated from primary tissues. This review focuses on the derivation and characterization of iNSCs and their biomedical applications. We first outline different approaches to generate iNSCs and then discuss the underlying molecular mechanisms. Finally, we summarize the preclinical validation of iNSCs to highlight that these cells are promising targets for disease modeling, autologous cell therapy, and precision medicine. Take the shortcut: from iPSC to iNSCForced expression of lineage-specific transcription factors (TFs) has been shown to reprogram the developmental potential of various somatic cell types e.g. by inducing pluripotency [1]. The seminal breakthrough of fibroblast reprogramming into iPSCs offers a novel experimental tool to generate patient-specific cells for developmental studies and diverse biomedical applications, such as disease modeling and cell therapy. Since then, efficiency and robustness of reprogramming protocols have been substantially improved, but the derivation of patient-specific iPSCs remains a lengthy and cumbersome procedure. Moreover, clinical applications require subsequent redifferentiation of iPSCs into the cell type of interest, which is inefficient and risky because transplanted undifferentiated iPSCs are tumorigenic. In the shadow of iPSC-type reprogramming, second-generation reprogramming paradigms have been developed to bypass the pluripotency state Abbreviations

Transplantation of induced neural stem cells (iNSCs) into chronically demyelinated corpus callosum ameliorates motor deficits

“…Induced neural stem cells (iNSCs) have the potential to self-renew and to differentiate along three neural lineages [29,31,32,51]. Following revival and expansion, iNSCs were assessed for self-renewal as neurospheres ( Fig.…”

“…The objective of the current study was to employ a combination of translational approaches to evaluate induced neural stem cell (iNSC) transplantation after chronic demyelination. Direct conversion of mouse or human somatic cells to generate iNSCs circumvents the pluripotent stage associated with increased tumorigenesis and genomic instability, with potential as an autologous therapy [29][30][31][32]. To model an autologous set-up, we transplanted syngeneic iNSCs into the CC after 12 weeks of CPZ in two cohorts of mice.…”

Imaging Analysis and Evaluation of Neural Stem Cell Intracerebral Migration and Functional Reconstruction Based on Deep Learning

“…This traditional understanding has now been completely broken [14]- [16]. Relevant scholars have successfully isolated NSC from adult rat striatum using serum-free medium [17]. The cells of most cell types of the nervous system have the ability to respond to injuries and diseases, breaking the view that the adult central nervous system cannot be repaired after injury [18], [19].…”

Stem cell reprogramming: blood, neurons, and beyond

“…In this Special Issue of FEBS Letters entitled 'Neural and Hematopoietic Stem Cell Reprogramming', we present a collection of peer-reviewed original articles and reviews authored by select international experts. They discuss the most exciting recent developments in the field, focusing on hematopoietic [1][2][3][4][5] and neural [6][7][8][9][10] (stem) cell generation/reprogramming in vitro. The future research directions and the obstacles ahead are also put into perspective.…”

“…In short, Chen et al [1] discuss the recent progress in blood cell reprogramming and the potential use of these cells for disease modeling and therapeutic development; Dur an et al [2] compare and discuss the reprogramming methods used to generate hematopoietic stem and progenitor cells; Daniel et al [3] describe an improved human hemogenic induction protocol for establishing an in vitro model of human hematopoiesis, which may facilitate disease modeling and provide a basis for a platform for cell-based therapeutics; Hansen et al [4] discuss the derivation of erythroid, megakaryoid, and myeloid cells from iPSCs and the obstacles currently hindering therapeutic use; Menegatti et al [5] review the complex transcriptional network regulating blood cell generation during embryonic development and how this information can help in generating these cells in vitro; Traxler et al [6] report the most recent advances in direct induced neural (iN) conversion and compare this to other reprogramming-based neural cell models; Greiner et al [7] highlight the implications of sex-related intrinsic mechanisms and different adult stem cell populations (e.g., mesoderm-derived stem cells, neural stem cells, neural crest-derived stem cells) for stem cell differentiation and regeneration and for the design of new treatment options; Erharter et al [8] discuss different approaches to generate induced neural stem cells (iNSCs) and their promising use for disease modeling, autologous cell therapy, and personalized medicine; Birtele et al [9] report that adding neuronal-specific microRNAs into different culture media improves neuronal maturation and the acquisition of electrophysiological properties during direct neural reprogramming; and finally, Denoth-Lippuner and Jessberger [10] take a broader perspective discussing how reprogramming might lead to the rejuvenation of a cell, an organ, or even the whole organism.…”