Direct pericyte-to-neuron reprogramming via unfolding of a neural stem cell-like program

Karow, Marisa; Camp, J. Gray; Falk, Sven; Gerber, Tobias; Pataskar, Abhijeet; Gac-Santel, Malgorzata; Kageyama, Jorge; Brazovskaja, Agnieska; Garding, Angela; Fan, Wenqiang; Riedemann, Therese; Casamassa, Antonella; Smiyakin, Andrej; Schichor, Christian; Götz, Magdalena; Tiwari, Vijay; Treutlein, Barbara; Berninger, Benedikt

doi:10.1038/s41593-018-0168-3

Cited by 104 publications

(95 citation statements)

References 55 publications

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“…Demonstration of the endogenous reprogrammability (trans‐differentiation) of pericytes to generate various interneurons was an important aspect of the current study. The reprogrammability of pericytes is consistent with a recent report on forced ectopic expression of Ascl1 and Sox2 that triggers direct conversion of pericytes into interneurons (Karow et al, ). The dormant neurogenic capacity of microvascular pericytes can be traced back to the developmental origin of these cells.…”

Section: Discussionsupporting

confidence: 90%

Neural microvascular pericytes contribute to human adult neurogenesis

Farahani

Rezaei-Lotfi

Simonian

et al. 2018

J of Comparative Neurology

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Consistent adult neurogenic activity in humans is observed in specific niches within the central nervous system. However, the notion of an adult neurogenic niche is challenged by accumulating evidence for ectopic neurogenic activity in other cerebral locations. Herein we interface precision of ultrastructural resolution and anatomical simplicity of accessible human dental pulp neurogenic zone to address this conflict. We disclose a basal level of adult neurogenic activity characterized by glial invasion of terminal microvasculature followed by release of individual platelet‐derived growth factor receptor‐β mural pericytes and subsequent reprogramming into NeuN+ local interneurons. Concomitant angiogenesis, a signature of adult neurogenic niches, accelerates the rate of neurogenesis by amplifying release and proliferation of the mural pericyte population by ≈10‐fold. Subsequent in vitro and in vivo experiments confirmed gliogenic and neurogenic capacities of human neural pericytes. Findings foreshadow the bimodal nature of the glio‐vascular assembly where pericytes, under instruction from glial cells, can stabilize the quiescent microvasculature or enrich local neuronal microcircuits upon differentiation.

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Section: Discussionsupporting

confidence: 90%

Neural microvascular pericytes contribute to human adult neurogenesis

Farahani

Rezaei-Lotfi

Simonian

et al. 2018

J of Comparative Neurology

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“…Neuroregeneration in adult mammalian CNS has been proved to be one of the most difficult tasks in the entire regenerative medicine field, largely because neurons cannot divide to regenerate themselves and external cell transplantation yields very low number of functional new neurons (Goldman, 2016). To overcome the limitations of cell transplantation therapy, we, together with other research groups, have developed in vivo cell conversion technology to regenerate functional new neurons from endogenous glial cells for brain repair (Chen et al, 2019; Gascon et al, 2016; Guo et al, 2014; Karow et al, 2018; Liu et al, 2015; Niu et al, 2015; Niu et al, 2018; Pereira et al, 2017; Torper et al, 2015; Wang et al, 2016; Zhang et al, 2018). While stab injury model has been commonly used in various in vivo cell conversion studies, we have previously demonstrated in a mouse Alzheimer’s disease model that NeuroD1 can convert reactive astrocytes into functional neurons in 14-month old AD mouse brains (Guo et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Neuroregeneration to Treat Ischemic Stroke in Adult Non-Human Primate Brains through NeuroD1 AAV-based Gene Therapy

Yang

Feng

et al. 2019

Preprint

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Stroke is a leading cause of death and disability but most of the clinical trials have failed in the past, despite our increasing understanding of the molecular and pathological mechanisms underlying stroke. While many signaling pathways have been identified in the aftermath of stroke, the majority of current approaches are focusing on neural protection rather than neuroregeneration. In this study, we report an in vivo neural regeneration approach to convert brain internal reactive astrocytes into neurons through ectopic expression of a neural transcription factor NeuroD1 in adult non-human primate (NHP) brains following ischemic stroke. We demonstrate that NeuroD1 AAV-based gene therapy can convert reactive astrocytes into neurons with high efficiency (90%), but astrocytes are never depleted in the NeuroD1-expressed areas, consistent with the proliferative capability of astrocytes. The NeuroD1-mediated in vivo astrocyte-to-neuron (AtN) conversion in monkey cortex following ischemic stroke increased local neuronal density, reduced reactive microglia, and surprisingly protected parvalbumin interneurons in the converted areas. The NeuroD1 gene therapy showed a broad time window, from 10 days to 30 days following ischemic stroke, in terms of exerting its neuroregenerative and neuroprotective effects. The cortical astrocyte-converted neurons also showed Tbr1+ cortical neuron identity, similar to our earlier findings in rodent animal models. Unexpectedly, NeuroD1 expression in converted neurons showed a significant decrease after 6 months of viral infection, suggesting a potential self-regulatory mechanism of NeuroD1 in adult mature neurons of NHPs. These results suggest that in vivo cell conversion through NeuroD1-based gene therapy may be an effective approach to regenerate new neurons in adult primate brains for tissue repair.

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“…The most prominent conversion strategies using BAM, Ascl1/ Ngn2, and miR-9/9*-124 typically give rise to a major population of excitatory glutamatergic neurons, and the Ngn2-only protocols lead to excitatory cholinergic neurons ( Fig. Ascl1/Sox2-based iNs generated from pericytes in vivo resemble mixed GABAergic/glutamatergic cultures [69], and Ascl1 has been shown to induce oligodendroglial cells from adult neural stem cells in the dentate gyrus of mice [70]. While these observations somewhat imply a glutamatergic-by-default mechanism, or alternatively have led to the assumption that Ascl1 and Ngn2 are pro-glutamatergic and pro-cholinergic, respectively, reality appears less straightforward.…”

Section: Subtype-specific In Conversionmentioning

confidence: 99%

“…For example, iNs generated from iPSCs through Ngn2-only protocols are predominantly glutamatergic [16,68]. Ascl1/Sox2-based iNs generated from pericytes in vivo resemble mixed GABAergic/glutamatergic cultures [69], and Ascl1 has been shown to induce oligodendroglial cells from adult neural stem cells in the dentate gyrus of mice [70]. Also, both TFs are involved in midbrain and hindbrain neuronal differentiation and have varying capacities depending on the regional context [71,72].…”

Section: Subtype-specific In Conversionmentioning

confidence: 99%

“…With the establishment of (epi)genomic sequencing and epigenetic array technologies, single-cell technologies, and new insights into the complexity of neurological diseases, the historic neuron-electrophysiologycentric view on neuronal identity, function, and disease is fading [35,51,69,116]. Thus, also a broadened set of criteria on how to characterize a neuron using such new omics technologies in addition to the classical cell biological and electrophysiological measures is uprising (Fig.…”

Section: Updating Our Criteria To Define Neuronsmentioning

confidence: 99%

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Next‐generation disease modeling with direct conversion: a new path to old neurons

2019

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Within just over a decade, human reprogramming-based disease modeling has developed from a rather outlandish idea into an essential part of disease research. While iPSCs are a valuable tool for modeling developmental and monogenetic disorders, their rejuvenated identity poses limitations for modeling age-associated diseases. Direct cell-type conversion of fibroblasts into induced neurons (iNs) circumvents rejuvenation and preserves hallmarks of cellular aging. iNs are thus advantageous for modeling diseases that possess strong age-related and epigenetic contributions and can complement iPSCbased strategies for disease modeling. In this review, we provide an overview of the state of the art of direct iN conversion and describe the key epigenetic, transcriptomic, and metabolic changes that occur in converting fibroblasts. Furthermore, we summarize new insights into this fascinating process, particularly focusing on the rapidly changing criteria used to define and characterize in vitro-born human neurons. Finally, we discuss the unique features that distinguish iNs from other reprogramming-based neuronal cell models and how iNs are relevant to disease modeling.

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Direct pericyte-to-neuron reprogramming via unfolding of a neural stem cell-like program

Cited by 104 publications

References 55 publications

Neural microvascular pericytes contribute to human adult neurogenesis

Neural microvascular pericytes contribute to human adult neurogenesis

In Vivo Neuroregeneration to Treat Ischemic Stroke in Adult Non-Human Primate Brains through NeuroD1 AAV-based Gene Therapy

Next‐generation disease modeling with direct conversion: a new path to old neurons

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