Induced Neural Stem Cells Achieve Long-Term Survival and Functional Integration in the Adult Mouse Brain

Abstract

SummaryDifferentiated cells can be converted directly into multipotent neural stem cells (i.e., induced neural stem cells [iNSCs]). iNSCs offer an attractive alternative to induced pluripotent stem cell (iPSC) technology with regard to regenerative therapies. Here, we show an in vivo long-term analysis of transplanted iNSCs in the adult mouse brain. iNSCs showed sound in vivo long-term survival rates without graft overgrowths. The cells displayed a neural multilineage potential with a clear bias toward astrocytes and a permanent downregulation of progenitor and cell-cycle markers, indicating that iNSCs are not predisposed to tumor formation. Furthermore, the formation of synaptic connections as well as neuronal and glial electrophysiological properties demonstrated that differentiated iNSCs migrated, functionally integrated, and interacted with the existing neuronal circuitry. We conclude that iNSC long-term transplantation is a safe procedure; moreover, it might represent an interesting tool for future personalized regenerative applications.

Recent achievements in stem cell-mediated myelin repair

“…Another important question to be solved is to what degree such cells retain an increased tumorigenic potential based on their modulation via oncogenic factors. Although Wang et al [100] did not detect any tumors within a 9-month period post grafting of human iPSC-derived OPCs into myelin-deficient shiverer mice, further studies explored the underlying mechanisms of carcinoma formation [107][108][109][110]. In a similar vein, migration of transplanted cells appears to be limited but was found to be stimulated following overexpression of the polysialylated neural cell adhesion molecule concomitantly with the generation of myelin in demyelinated corpus callosum [111].…”

In vivophenotyping of Parkinson-specific stem cells reveals increased a-Synuclein levels but no spreading

“…Two weeks before transplantation, 10 µg 6-OHDA (6-Hydroxydopamine hydrobromide, Sigma Aldrich) was stereotactically injected into the striatum using following coordinates in relation to bregma: anteroposterior: 0.5 mm, mediolateral: 2.0 mm, dorsoventral: 3.5 mm (below skull). Transplantation of NESCs was performed as described before (Hemmer et al, 2014;Reinhardt et al, 2013a). In brief, NESCs (Passage 10-13) were differentiated towards dopaminergic neurons for 6 days.…”

Generation of diverse neural cell types through direct conversion

“…Generation of neural cell types through direct conversion has been studied extensively in vitro, with confirmed long-term survival and functional integration following transplantation [126] . As such, investigations have expanded into generation of neural cells through direct conversion in vivo, in which cells are directly converted within their native physiological environment [127] .…”