Generation of neural stem cells from adult astrocytes by using a single reprogramming factor

Zarei-Kheirabadi, Masoumeh; Hesaraki, Mehdi; Shojaei, Amir; Kiani, Sahar; Baharvand, Hossein

doi:10.1002/jcp.28510

Cited by 14 publications

(8 citation statements)

References 35 publications

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“…A key question to assess the outcome of direct conversion strategies is to which extent directly converted iNSCs recapitulate these characteristics [11,71]. In order to demonstrate selfrenewal potential and clonal growth ability, iNSCs were either cultivated as primary and secondary neurospheres [33,34], analyzed in colony formation assays [28,33,36,39,42,48,72], and/or passaged several times [11,13,14,26,30,32,33,38,57,59,60,73]. On the other hand, all iNSC populations have been reported to express pan-neural markers, to be at least bipotential, and to show self-renewal and clonal growth ( Table 2).…”

Section: Molecular and Cellular Characterization Of Inscsmentioning

confidence: 99%

“…Several groups succeeded in direct OSKM-and BSKM-independent conversion of somatic cells into iNSCs [12,28,[36][37][38]. Two studies reported the generation of iNSCs from human fibroblasts through inducible lentiviral transduction of Zfp521, a neurogenic TF, of cells cultured under hypoxic conditions in a reprogramming medium that contained valproic acid, CHIR99021, and SB431542 [36,39]. Another approach allowed to directly converting mouse and human fibroblasts, including cells derived from AD patients, into iNSCs with an efficiency higher than 0.5% [38].…”

Section: Transcription Factors Employed In Insc Generationmentioning

confidence: 99%

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

et al. 2019

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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

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Section: Molecular and Cellular Characterization Of Inscsmentioning

confidence: 99%

Section: Transcription Factors Employed In Insc Generationmentioning

confidence: 99%

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

et al. 2019

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“…In addition, Zfp521 is a key factor in inducing differentiation of mouse embryonic stem cells into neural progenitors and its knockdown leads to inhibition of neural differentiation [42]. Zfp521 has been shown to be sufficient for the direct conversion of cultured human and mouse fibroblasts [31] as well as mouse astrocytes [32] into NSCs. Moreover, in comparison with Sox2 overexpression, Zfp521 demonstrated a higher efficiency in the conversion of astrocytes into iNSCs.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we demonstrated that a single zinc-finger transcription factor, Zfp521, is sufficient for direct conversion of human and mouse fetal-and neonatal-derived fibroblasts into proliferating and multipotent iNSCs [31]. Our recent study indicated that mouse brain astrocytes could be reprogrammed in vitro to iNSCs by Zfp521 [32]. Since reprogramming efficiencies of ectopic transcription factors may differ in vivo, it is unclear whether Zfp521 can convert the fate of astrocytes in the adult rat spinal cord and improve function following SCI.…”

Section: Introductionmentioning

confidence: 99%

In vivo conversion of rat astrocytes into neuronal cells through neural stem cells in injured spinal cord with a single zinc-finger transcription factor

et al. 2019

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Background: Spinal cord injury (SCI) results in glial scar formation and irreversible neuronal loss, which finally leads to functional impairments and long-term disability. Our previous studies have demonstrated that the ectopic expression of Zfp521 reprograms fibroblasts and astrocytes into induced neural stem cells (iNSCs). However, it remains unclear whether treatment with Zfp521 also affects endogenous astrocytes, thus promoting further functional recovery following SCI. Methods: Rat astrocytes were transdifferentiated into neural stem cells in vitro by ZFP521 or Sox2. Then, ZFP521 was applied to the spinal cord injury site of a rat. Transduction, real-time PCR, immunohistofluorescence, and function assessments were performed at 6 weeks post-transduction to evaluate improvement and in vivo lineage reprogramming of astrocytes. Results: Here, we show that Zfp521 is more efficient in reprogramming cultured astrocytes compared with Sox2. In the injured spinal cord of an adult rat, resident astrocytes can be reprogrammed into neurons through a progenitor stage by Zfp521. Importantly, this treatment improves the functional abilities of the rats as evaluated by the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale and further by calculation of its subscores. There was enhanced locomotor activity in the hind limbs, step length, toe spread, foot length, and paw area. In addition, motor evoked potential recordings demonstrated the functional integrity of the spinal cord. Conclusions: These results have indicated that the generation of iNSCs or neurons from endogenous astrocytes by in situ reprogramming might be a potential strategy for SCI repair.

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“…Transcription factors are proteins that either up-regulate or down-regulate the transcription of specific genes, generally by interacting with the RNA polymerase's transcription complex or by down-regulating others factors involved in stimulating transcription [194][195][196][197][198]. Currently, the reprograming of astrocytes into neurons may be performed with simpler procedures that overexpress a single transcription factor [193,199]. MicroRNAs are noncoding sequences of RNA (often of about 22 nucleotides) that may regulate gene expression at the posttranscriptional level, generally by selectively binding to a particular mRNA which produces the silencing of a specific RNA [200,201].…”

Section: The Global Activation Of the Neuroprotective Functions Of Astrocytesmentioning

confidence: 99%

Astrocytes, a Promising Opportunity to Control the Progress of Parkinson’s Disease

et al. 2021

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At present, there is no efficient treatment to prevent the evolution of Parkinson’s disease (PD). PD is generated by the concurrent activity of multiple factors, which is a serious obstacle for the development of etio-pathogenic treatments. Astrocytes may act on most factors involved in PD and the promotion of their neuroprotection activity may be particularly suitable to prevent the onset and progression of this basal ganglia (BG) disorder. The main causes proposed for PD, the ability of astrocytes to control these causes, and the procedures that can be used to promote the neuroprotective action of astrocytes will be commented upon, here.

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Generation of neural stem cells from adult astrocytes by using a single reprogramming factor

Cited by 14 publications

References 35 publications

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

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

In vivo conversion of rat astrocytes into neuronal cells through neural stem cells in injured spinal cord with a single zinc-finger transcription factor

Astrocytes, a Promising Opportunity to Control the Progress of Parkinson’s Disease

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