|Year : 2020 | Volume
| Issue : 6 | Page : 973-979
Adult neurogenesis from reprogrammed astrocytes
Brian B Griffiths PhD
, Anvee Bhutani, Creed M Stary
Department of Anesthesiology, Pain & Perioperative Medicine, Stanford University School of Medicine, Stanford, CA, USA
|Date of Submission||12-Aug-2019|
|Date of Decision||15-Aug-2019|
|Date of Acceptance||28-Sep-2019|
|Date of Web Publication||10-Dec-2019|
Brian B Griffiths
Department of Anesthesiology, Pain & Perioperative Medicine, Stanford University School of Medicine, Stanford, CA
Source of Support: This work was supported by the American Heart Association, No. 18POST33990395 (to BBG), American Heart Association, No.
14FTF-19970029 (to CMS), and National Institutes of Health, No. NS107445 (to CMS), Conflict of Interest: None
The details of adult neurogenesis, including environmental triggers, region specificity, and species homology remain an area of intense investigation. Slowing or halting age-related cognitive dysfunction, or restoring neurons lost to disease or injury represent just a fraction of potential therapeutic applications. New neurons can derive from stem cells, pluripotent neural progenitor cells, or non-neuronal glial cells, such as astrocytes. Astrocytes must be epigenetically “reprogrammed” to become neurons, which can occur both naturally in vivo, and via artificial exogenous treatments. While neural progenitor cells are localized to a few neurogenic zones in the adult brain, astrocytes populate almost every brain structure. In this review, we will summarize recent research into neurogenesis that arises from conversion of post-mitotic astrocytes, detail the genetic and epigenetic pathways that regulate this process, and discuss the possible clinical relevance in supplementing stem-cell neurogenic therapies.
Keywords: astrocyte; brain; dedifferentiation; development; disease; glia; injury; neurogenesis
|How to cite this article:|
Griffiths BB, Bhutani A, Stary CM. Adult neurogenesis from reprogrammed astrocytes. Neural Regen Res 2020;15:973-9
| Introduction|| |
Neurogenesis is the birth of new neurons in the brain and includes the assumption that some of the newly born neurons will successfully integrate into functional synaptic networks, while those that is not will be recycled. The brain undergoes a high degree of neurogenesis during initial development, which precipitously drops during adulthood but does not disappear completely. As a relatively newly discovered phenomenon, much remains unknown about the underlying causes or the potential clinical relevance of adult neurogenesis. Initial evidence suggests that the function inclusion of new neurons helps maintain normal brain functioning, and can help reverse cognitive losses due to aging, disease, or injury. New neurons can derive from stem cells and pluripotent neural progenitor cells, though both of these populations decline in an aging brain. Neurogenesis from non-neuronal glial cells, such as astrocytes, has recently gained interest because while neural progenitor cells are limited to a few neurogenic zones, astrocytes are common in almost every area of the adult brain. Astrocyte-derived neurogenesis requires epigenetic “reprogramming,” which happens both naturally after injury and in response to exogeneous stimuli. Unraveling the genetic pathways within astrocytes that can be manipulated to induce a phenotypical change is vital to using astrocytes as a therapeutic source of new neurons. This review will summarize recent research in astrocyte-derived neurogenesis, the known mechanisms and signaling pathways, and potential therapeutic applications.
Classic neurogenesis background
Neurogenesis is robust during early brain development, with neural stem cells giving rise to radial glial cells, which serve as progenitors for neurons and astrocytes. Historically adult brains were thought to contain a finite number of neurons, with neuronal “plasticity” limited to neuronal loss from aging, disease, or injury. In the early 1990s, researchers reported that new neurons could be cultured in vitro from adult brain tissue of rodents (Richards et al., 1992), followed shortly by in vivo observations of these same processes in rodents (Palmer et al., 1997). The interspecies homology of neurogenesis was established by the discovery that non-human primates and human adults also exhibit in vivo neurogenesis (Eriksson et al., 1998). The regions that retain neurogenic abilities remain an area of controversy, but it is generally agreed that in the adult mammalian brain new neurons are plentiful in the subventricular zone (including the olfactory bulb), and the subgranular zone of the dentate gyrus in the hippocampus (Gage, 2002). However, new neurons have been reported in many other brain areas, such as the striatum (Ernst et al., 2014), cortex (Magavi et al., 2000), and hypothalamus (Kokoeva et al., 2005), and others, and it has been hypothesized that adult neural progenitors “may not be as restricted as implied by their normal location and function” (Palmer et al., 1997). The source of these new neurons outside of canonical neurogenic regions remains a topic of active investigation. Since its first discovery, many facets of adult neurogenesis have been uncovered [for recent reviews, see Augusto-Oliveira et al. (2019); Lei et al. (2019)].
Recent controversy in adult neurogenesis
The natural ability of adult mammalian brains to create new neurons has experienced rekindled controversy with a recent study by Sorrells et al. (2018) that posits hippocampal neurogenesis begins to decrease in early childhood and is not at all present in adult humans or adult non-human primates. The study was widely disseminated and disputes the foundational work for neurogenesis with the hypothesis that human brains may be fundamentally different than those of other species. Paredes et al. (2016) expanded on this argument, describing a possible negative correlation between brain size and potential for neurogenesis. In contrast, Boldrini et al. (2018) concluded that in non-diseased adult hippocampal cells, neurogenesis continues to occur despite aging. They were unable to compare their results directly as the previous studies used thin sections (5 µm) without stereology, and subjected the tissue to low temperatures/pH. More recently, Moreno-Jiménez et al. (2019) corroborated neurogenesis in adult humans, describing hippocampal neurogenesis in neurologically healthy subjects using similar immunohistochemical techniques as Sorrells et al. (2018). They attributed the lack of neurogenesis markers in the original study to methodological problems related to a delayed timing and over-fixation of brain tissue, and that a major marker of new neurons—doublecortin—loses antigenicity after 12 hours of fixation time. In our lab, we have also seen a reduction of doublecortin antigenicity and much higher background staining with fixation time, with increased fluorescent signal after ~12 hour fixations [Figure 1]A compared to ~3 day fixations [Figure 1]B. Others have called into question the relevance of adult neurogenesis in inbred laboratory rodents to real world behavior (Oppenheim, 2019). These debates raise interesting methodological questions in how best to quantify new neurons and what exactly constitutes proof of adult neurogenesis, challenging a comprehensive body of literature that details timing, environmental conditions, genetic contributions, and epigenetic regulation of adult neurogenesis in humans. Future studies delineating technical approaches with increased specificity and sensitivity to quantify new neurons in the adult human brain are therefore required to advance the therapeutic potential of neurogenesis.
|Figure 1: Doublecortin expression in the dentate gyrus.|
(A) Doublecortin immunofluorescence at ~12 hour fixation with 4% paraformaldehyde or (B) ~3 day fixation with 4% paraformaldehyde, highlighting the methodological difficulties in using doublecortin as a marker of neurogenesis in over-fixed tissue.
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Neurogenesis as a therapeutic endpoint
Neurogenesis has been a long-standing goal to restore brain function for a host of illnesses and diseases with varying levels of success. In hypoxic-ischemic injuries, such as stroke, the subventricular zone of the brain has been shown to regenerate neocortical neurons in neonatal rodents, suggesting this could be an effective therapy (Yang et al., 2007). In Alzheimer’s disease, doublecortin expression decreases, a phenomenon that may directly contribute to the loss of memory that is commonly associated with the disease, and which may be slowed or reversed by promoting neurogenesis (Moreno-Jiménez et al., 2019). This hypothesis is supported by prior work utilizing the neurosteroid alloprognanalone to promote neurogenesis in in vitro and in vivo rodent Alzheimer’s models, as well as in human cell samples (Brinton and Wang, 2006). Increasing neurogenesis has been shown to work as an therapy to restore cognitive function in rodents subjected to traumatic brain injury, especially when given in conjunction with the neuroprotective drug erythropoietin (Lu et al., 2005). Studies in non-human primates have suggested neurogenesis is essential for effective usage of antidepressant medication, with new hippocampal neurons serving as a marker for treatment efficacy (Perera et al., 2011). In rodent models of Down syndrome, an altered generation of neurons was shown to have been a successful treatment to render mice with normal cognitive function as compared to mice without such treatment (Nakano-Kobayashi et al., 2017). There are sex differences in many diseases and illnesses, and growing evidence that these differences extend to neurogenesis, both as a phenomenon and a therapeutic endpoint, as well (Yagi and Galea, 2019). Finally, there are several active clinical trials assessing the effect of neurogenesis on disorders and diseases including schizophrenia, stroke, and traumatic brain injury (ClinicalTrials.gov, National Library of Medicine (U.S.), 2019).
Neurogenesis is heavily regulated by astrocytes
Astrocytes are non-neuronal glial cells that have been increasingly recognized as important regulators of brain function and disease (Liddelow and Sofroniew, 2019). Adult neural stem cells (aNSCs) in the canonical neurogenic zones are both positively and negatively regulated by contact with astrocytes (Cassé et al., 2018). These astrocytes influence whether aNSCs mature into neurons through membrane-membrane and extracellular signaling (Lim and Alvarez-Buylla, 1999). Migration and forming of synaptic connections of new neurons can also be also influenced by astrocytes. Signaling from astrocytes drastically increases both the proliferation of aNSCs and their commitment to a neuronal fate (Song et al., 2002). However, the degree to which astrocytes promote neurogenesis is modulated by the body’s response to environmental conditions. For example, inflammation can result in lower numbers of new neurons through altered astrocytic production of interleukin-6 production in adult mice (Vallières et al., 2002). Astrocytes become “reactive” during injury, which results in a drastic change in their cellular programming, and may affect their ability to regulate aNSCs (Cassé et al., 2018). The level of astrocyte control over neurogenesis also extends beyond neural stem cells; oligodendrocyte precursors cells are common in the brain and serve to replenish the stock of myelin-contributing glial cells (Simon et al., 2011), but can be diverted from an oligodendrocyte fate by astrocyte signals (Gaughwin et al., 2006). Most interestingly, this level of control over the cell fate of non-neuronal cells even extends to astrocytes themselves.
| Search Strategy and Selection Criteria|| |
Studies included in this review were found on the Google Scholar and PubMed databases, between March 2019 and August 2019, using the search terms: dedifferentiated astrocytes, reprogrammed astrocytes, adult neurogenesis, dedifferentiation, and various combinations of the above phrases.
| Neurogenesis from Dedifferentiated Astrocytes|| |
Unlike neurons, glial cells readily proliferate to maintain stable numbers in the brain. Before reaching full maturity, astrocyte progenitors maintain their ability to change their cell fate, and the conversion of radial glia to astrocytes appears to be bidirectional (Hunter and Hatten, 1995). The process of regressing to a previous, less-specialized cell fate is known as “dedifferentiation”. These cells can then differentiate back into a specialized cell, though not necessarily the same cell fate they previously occupied [Figure 2]. In adults, astrocytes can still enter periods of lability after injury, during the period of “reactive gliosis”. In a stab wound model, up to 50% of astrocytes reentered the cell cycle between three days and a week after injury, a portion of which proliferated to create more astrocytes around the site of injury (Simon et al., 2011). Within the brain, these labile cells are usually pushed back to an astrocyte cell fate (Buffo et al., 2008); however, several in vitro studies have demonstrated that a subset of astrocytes that have reentered the cell cycle can dedifferentiate and reprogram into neurons in response to injury (Buffo et al., 2008; Yang et al., 2009; Robel et al., 2011; Magnusson et al., 2014) or environmental stressors (Yu et al., 2006). In neurogenic regions of the brain, some neurons are born from astrocytes even under normal conditions (Seri et al., 2001). In addition to astrocytes, the capacity to dedifferentiate has been demonstrated in microglia, oligodendrocytes and radial glia (Grinspan et al., 1996; Yokoyama et al., 2004; Mori et al., 2005), suggesting the deprograming of these cells may share similar developmental origins and be an important property of a normally functioning brain. The transcriptional profiles of neural stem cells and reactive astrocytes share many similarities (Götz et al., 2015), but several different pathways have been found to play a role in the conversion of astrocytes to neurons.
|Figure 2: Neuronal and astrocyte development.|
Neural stem cells can renew, proliferate, or differentiate into neurons or astrocytes. After injury or disease in adulthood, some astrocytes can reenter the cell cycle.
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Many of the factors involved in differentiation are normally expressed in neural stem cells but cease expression after maturation. Immature astrocytes can be easily reprogramed into neurons through expression of Neurog1, Neurog2 and Mash1, and though these neurons grow more slowly than natural neurons, they still gain functional abilities when cultured with active cortical neurons (Berninger et al., 2007).
Changing the programing of adult astrocytes usually involves the expression of several different pathways, epigenetic silencing of mature astrocyte genes, and removing silencing marks from progenitor genes to restore a pluripotent state (Robel et al., 2011). For example, increased acetylation of H3K9K14 near NeuroG1 and NeuroG2 is observed during astrocyte dedifferentiation in mouse primary neuronal cultures (Hirabayashi et al., 2009). Interestingly, many of the downstream targets of these two transcription factors do not seem to be silenced themselves, and forced expression can directly lead to astrocyte dedifferentiation (Robel et al., 2011). Inhibiting the actions of DNA methyltransferases, which normally silence genes as a cell matures, can keep stem cells from resuming an astrocytic phenotype (Bulstrode et al., 2017). In contrast, increasing expression of Ezh2, a histone methyltransferase that catalyzes H3K27me3 and leads to stable gene repression, is necessary but not sufficient to cause astrocyte dedifferentiation (Sher et al., 2010). By increasing Ezh2, genes necessary for astrocyte maintenance are silenced, and the cell resumes a partial NSC morphology. NeuroD4 was found to reprogram astrocytes to neurons, and blocking NeuroD4 with transcriptional repressors lead to the accumulation of H4K20me3 and astrocytes that did not dedifferentiate (Masserdotti et al., 2015).
Transcription factor pathways
Altering the expression of several other transcription factors and downstream targets has been observed to change astrocyte fate. In particular the transcription factors Nanog Homeobox, POU Class 5 Homeobox 1 (OCT4), Forkhead Box G1 (FOXG1), SRY-Box 2 (SOX2), and Cell Cycle Exit and Neuronal Differentiation 1 (CEND1) all have the capability, either alone or in concert with each other, to dedifferentiate post-mitotic astrocytes (Corti et al., 2012; Niu et al., 2013; Aravantinou-Fatorou et al., 2015; Bulstrode et al., 2017). This effect is further increased when astrocytes are treated with epidermal growth factor (EGF- and fibroblast growth factor-rich media. Forkhead Box O3, a transcription factor regulated by FOXG1/SOX2, is highly expressed in mature astrocytes, and transcription repression by FOXG1/SOX2 is partly responsible for reversion to a aNSC phenotype (Bulstrode et al., 2017). Another necessary-but-not-sufficient factor is fibroblast growth factor 4, a mitogen important for cell proliferation that pushes NSCs toward a neural fate (Feng et al., 2014). Re-expression of the transcriptional repressor (BMI1) in differentiated astrocytes resulted in their reversion to NSC-like cells, and they produced the NSC markers nestin, CD133, and SOX2 (Moon et al., 2008). Furthermore, these cells can then differentiate back into astrocytes or become neurons or oligodendrocytes. Activation of the NF-κB pathway via the introduction of tumor necrosis factor-positive media has been shown to cause GFAP+ astrocytes to re-express immature neuronal markers CD44, Musashi-1, and OCT4 (Gabel et al., 2016) in mature astrocyte cultures and in vivo brains. Sonic Hedgehog signaling acts in concert with OCT4 to increase astrocyte reprogramming (Yang et al., 2019). Astrocytes that express bone morphogenetic protein 4 were susceptible to dedifferentiation through noggin exposure (Michelucci et al., 2016). Overexpression of Cyclin-dependent kinase 6 in mature astrocytes resulted in a higher motility and a morphology representative of a more dedifferentiated state (Slomiany et al., 2006). Induction of the growth factor Erb-B2 Receptor Tyrosine Kinase 2 can cause astrocytes to revert to radial glial cells in the cortex, which then proliferate and become neurons (Ghashghaei et al., 2007; Yang et al., 2011). A combination of transcription factors and a microRNA—collective referred to as NeAL218 and consisting of NEUROD1, ASCL1, LMX1A, and the microRNA miR-218—reprogrammed astrocytes to neurons in both cell culture and in vivo experiments (Rivetti di Val Cervo et al., 2017). In addition to OCT4 and SOX2, the transcription factors Kruppel Like Factor 4 and MYC Proto-Oncogene have also been observed to participate in the dedifferentiation of astrocytes (Ruiz et al., 2010).
Intracellularly, aNSCs mature into neurons through multiple, complex changes in gene expression. MicroRNAs are small non-coding transcripts ~22–23 nucleotides long that inhibit the translation of mRNA and often target many members of the same regulatory pathway, with some having over a thousand putative targets. Change in microRNA expression driven by extracellular signals facilitate the transition of aNSCs to differentiated states (Stappert et al., 2018). Several miRNAs have been found to work in concert to drive this process, and afterwards maintain specialized gene expression patterns through the inhibition of proliferative genes. Let-7b is highly expressed in both differentiated neurons and astrocytes and regulates proliferation and differentiation (Zhao et al., 2010). miR-9 helps drive neural stem cells toward a neural fate (Zhao et al., 2009). Similarly miR-124, the most common microRNA in the brain (Lagos-Quintana et al., 2002), regulates the timing of neurogenesis in the canonical neurogenic zones (Cheng et al., 2009). Blocking miR-124 expression through the transcriptional repressor (REST) is essential to the development of astrocytes (Conaco et al., 2006). Treatment with miR-128, among other factors, was shown to increase astrocyte dedifferentiation (Rivetti di Val Cervo et al., 2017). Two microRNAs, miR-302 and miR-367, in conjunction with the histone deacetylase inhibitor valproic acid, were successful in reprogramming adult astrocytes (Ghasemi-Kasman et al., 2015). Expression of miR-181a influences neural stem cells to an astrocyte fate, whereas inhibition of miR-181a produces more neurons (Xu et al., 2014). After injury, treatment with miR-181a inhibitor increases the number of new neurons in the rat hippocampus through increased neurogenesis, possibly through the increased conversion of astrocytes to neurons (Griffiths et al., 2019). Neurogenic properties of astrocytes are dependent on local environmental factors, including Notch signaling (Imayoshi et al., 2008; Magnusson et al., 2014) and CDON expression. CDON is normally silenced through interactions with MeCP2 in astrocytes (Yasui et al., 2013), however, in a recent study we observed a significant post-injury increase in CDON expression in animals treated with miR-181a inhibitor post-injury (Griffiths et al., 2019). Treatment with microRNA inhibitors or mimics after injury, when astrocytes are reactive, may help drive reactive, dedifferentiated astrocytes toward a neural fate.
Reprogrammed neuronal subtype
Neurons are vastly heterogenous, and the ability to create new neurons in response to injury or disease will rely on the ability to drive differentiation toward relevant neuronal subtypes. Dedifferentiated astrocytes can be directed toward either an excitatory glutamatergic fate with NeuroG2, or an inhibitory GABAergic phenotype with Dlx2 (Heinrich et al., 2010). In another study, the ability to selectively transform astrocytes into glutamatergic neurons did not result in their forming synaptic connections until the transcriptional repressor INSM1 was also expressed (Masserdotti et al., 2015), suggesting potential therapies may need multi-timepoint transcriptional control. Sonic Hedgehog signaling is present in reactive astrocytes that gain aNSC properties in a stab wound injury model, but not in models of stroke (Sirko et al., 2013), though both models have been shown to dedifferentiate astrocytes. This suggests astrocyte dedifferentiation may be a convergent consequent of separate gene regulation responses, depending on the mode of injury. Though many of the factors in this section work on several species tested, some worked exclusively on human or rodent astrocytes (Zhang et al., 2015) [Table 1]. Understanding the differences in the pathways for neuron type or species specificity will be important for developing and selecting appropriate treatments in the future.
Neurogenesis via astrocyte reprogramming has also been investigated for therapy purposes for a variety of conditions. Alzheimer’s disease leads to a drastic increase in reactive astrocytes, but not an increase in neurogenesis (Boekhoorn et al., 2006). In a model of Alzheimer’s disease, reactive astrocytes were easily reprogrammed to functional neurons (Guo et al., 2014). Parkinson’s disease results from the loss of dopaminergic neurons and replacing lost dopaminergic neurons with reprogrammed astrocytes results in improved motor behavior in a mouse model and in human cells (Rivetti di Val Cervo et al., 2017). It is also a promising therapy for stroke patients, as astrocytes are more resilient to the loss of oxygen that results in wide-spread damage to neurons (Chouchane and Costa, 2012). In a stroke model, self-renewal and dedifferentiated astrocytes were seen in the cortical peri-infarct area (Shimada et al., 2012). Additionally, thousands of new neurons appear in the striatum in the weeks following stroke (Arvidsson et al., 2002; Zhang et al., 2009; Li and Clevers, 2010; Magnusson et al., 2014), and one- to two-thirds of the new neurons are estimated to have been generated from local astrocytes. In the presence of transplanted neural stem cells, astrocytes were observed to revert to a developmentally earlier programming and reform into radial glial cells to aid the migration of new neural stem cells (Leavitt et al., 1999). Though this review focuses on astrocyte dedifferentiation in the brain, there is parallel research being done on using astrocyte reprogramming to replace neurons in injured spinal cord (Su et al., 2014).
A particularly interesting case is injury sustained to the hippocampal CA1 after global cerebral ischemia (Li and Stary, 2016). After injury, neurons in the CA1 dwindle to almost undetectable levels, but reappear after several weeks of healing. The new CA1 cells have minimal observed BRDU labeling despite vast numbers of new neurons (Sugawara et al., 2000). Because of the absence of proliferating or migrating cells in CA1, these new neurons may be from dedifferentiated astrocytes. Reactive astrocytes after global cerebral ischemia are common in the CA1, while classic adult neurogenesis is not thought to occur in that brain region (Zeisel et al., 2015). Our own research suggests that dedifferentiating astrocytes may contribute to the neurogenesis seen in this injury model. The above cases are only a few of the currently research models, but astrocyte dedifferentiation has the potential to produce revolutionary therapies for a plethora of other disease and injuries.
Altering the genetic programming of astrocytes can also lead to negative consequences, such as their ability to develop into glioblastoma multiforme (Friedmann-Morvinski et al., 2012). Many gliomas are thought to be the result of natural astrocyte dedifferentiation gone wrong. Expression of transforming growth factor-α can lead to astrocyte dedifferentiation, but the resulting cells acquire oncogenic properties and become cancerous with even mild environmental stress (Dufour et al., 2009). Platelet-derived growth factor receptor, a protein commonly expressed in cancerous cells, was successful at dedifferentiating astrocytes and neurons, but also lead to cancerous phenotypes (Dufour et al., 2009). The expression of epidermal growth factor in the absence of tumor suppressor genes p16INK4a and p19ARF leads to astrocyte dedifferentiation and cancer (Bachoo et al., 2002). Additionally, it is very likely that forcing changes in expression of a few genes will not fully erase epigenetic regulation of all astrocyte-expressed genes, and they will retain a “memory” of their previous programming and exhibit altered phenotypes from naturally derived neurons (Tian et al., 2011). This may increase the risk of unintended gene expression even after a cell has matured and assumed normal functioning. However, understanding the pathways involved in astrocyte dedifferentiation and reprogramming may serve as a launching point for treating glioblastoma as well. Manipulation of these pathways can cause glioblastoma to stop their malignant proliferation and assume a more stem-cell like state (Dahan et al., 2014).
In addition to cancerous growths, the inclusion of new neurons into existing neuronal networks has the potential to disrupt functional signaling, introducing noise and dysregulation into a stable system. Many conditions that observe an increase in adult neurogenesis also note the phenomenon of “abberent neurogenesis”. For example, uncontrolled neurogenesis has been shown to play a role in the development of epilepsy (Jessberger et al., 2007; Cho et al., 2015). Stroke leads to an increase in adult neurogenesis, but many of the new neurons do not integrate properly and contribute to cognitive issues (Niv Fanny et al., 2012). Traumatic brain injury leads to a large increase in neurogenesis, but results atrophied astrocytes unable to regulate the new neurons (Robinson et al., 2016).
| Conclusions|| |
Finely controlled neurogenesis has the potential to benefit many disorders and diseases that result from the loss of healthy neurons. However, endogenous neural stem cell populations are limited to a few areas of the brain. Astrocytes are common throughout the brain, and new astrocytes are regenerated throughout the lifespan. Their natural ability to change their developmental programming back to an earlier state through dedifferentiation, transform into neurons, and integrate to form functional synapses within existing networks represents an exciting target for future researchers and clinicians. Advancing techniques to better quantify new neuron formation in the adult human brain are needed to advance clinical implementation. Notably, many devastating cancers are caused by uncontrolled astrocyte dedifferentiation. While this represents a substantial consideration and off-target effect of clinical neurogenic approaches, astrocyte-based diseases might also provide a model to further delineate astrocyte-mediated neurogenesis.
Author contributions: All authors wrote the manuscript and approved the final manuscript.
Conflicts of interest: The authors declare no conflicts of interest.
Financial support: This work was supported by the American Heart Association, No. 18POST33990395 (to BBG), American Heart Association, No. 14FTF-19970029 (to CMS), and National Institutes of Health, No. NS107445 (to CMS).
Copyright license agreement: The Copyright License Agreement has been signed by all authors before publication.
Plagiarism check: Checked twice by iThenticate.
Peer review: Externally peer reviewed.
Open peer reviewers: Tetsuro Ishii, University of Tsukuba, Japan; Hans-Gert Bernstein, University of Magdeburg, Germany; Randall L. Davis, Oklahoma State University, USA; Ivan Fernandez-Vega, Hospital Universitario Central de Asturias, Spain.
Funding: This work was supported by the American Heart Association, No. 18POST33990395 (to BBG), American Heart Association, No. 14FTF-19970029 (to CMS), and National Institutes of Health, No. NS107445 (to CMS).
| References|| |
Aravantinou-Fatorou K, Ortega F, Chroni-Tzartou D, Antoniou N, Poulopoulou C, Politis PK, Berninger B, Matsas R, Thomaidou D (2015) CEND1 and NEUROGENIN2 reprogram mouse astrocytes and embryonic fibroblasts to induced neural precursors and differentiated neurons. Stem Cell Rep 5:405-418.
Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8:963-970.
Augusto-Oliveira M, Arrifano GPF, Malva JO, Crespo-Lopez ME (2019) Adult hippocampal neurogenesis in different taxonomic groups: Possible functional similarities and striking controversies. Cells 8:125.
Bachoo RM, Maher EA, Ligon KL, Sharpless NE, Chan SS, You MJ, Tang Y, DeFrances J, Stover E, Weissleder R, Rowitch DH, Louis DN, DePinho RA (2002) Epidermal growth factor receptor and Ink4a/Arf: Convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 1:269-277.
Berninger B, Costa MR, Koch U, Schroeder T, Sutor B, Grothe B, Götz M (2007) Functional properties of neurons derived from in vitro reprogrammed postnatal astroglia. J Neurosci 27:8654-8664.
Boekhoorn K, Joels M, Lucassen PJ (2006) Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus. Neurobiol Dis 24:1-14.
Boldrini M, Fulmore CA, Tartt AN, Simeon LR, Pavlova I, Poposka V, Rosoklija GB, Stankov A, Arango V, Dwork AJ, Hen R, Mann JJ (2018) Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell 22:589-599.e5.
Brinton RD, Wang JM (2006) Therapeutic potential of neurogenesis for prevention and recovery from Alzheimer’s disease: allopregnanolone as a proof of concept neurogenic agent. Curr Alzheimer Res 3:185-190.
Buffo A, Rite I, Tripathi P, Lepier A, Colak D, Horn AP, Mori T, Götz M (2008) Origin and progeny of reactive gliosis: A source of multipotent cells in the injured brain. Proc Natl Acad Sci U S A 105:3581-3586.
Bulstrode H, Johnstone E, Marques-Torrejon MA, Ferguson KM, Bressan RB, Blin C, Grant V, Gogolok S, Gangoso E, Gagrica S, Ender C, Fotaki V, Sproul D, Bertone P, Pollard SM (2017) Elevated FOXG1 and SOX2 in glioblastoma enforces neural stem cell identity through transcriptional control of cell cycle and epigenetic regulators. Genes Dev 31:757-773.
Cassé F, Richetin K, Toni N (2018) Astrocytes’ contribution to adult neurogenesis in physiology and Alzheimer’s disease. Front Cell Neurosci 12:432.
Cheng LC, Pastrana E, Tavazoie M, Doetsch F (2009) miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nat Neurosci 12:399-408.
Cho KO, Lybrand ZR, Ito N, Brulet R, Tafacory F, Zhang L, Good L, Ure K, Kernie SG, Birnbaum SG, Scharfman HE, Eisch AJ, Hsieh J (2015) Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat Commun 6:1-13.
Chouchane M, Costa MR (2012) Cell therapy for stroke: use of local astrocytes. Front Cell Neurosci 6:49.
Conaco C, Otto S, Han JJ, Mandel G (2006) Reciprocal actions of REST and a microRNA promote neuronal identity. Proc Natl Acad Sci U S A 103:2422-2427.
Corti S, Nizzardo M, Simone C, Falcone M, Donadoni C, Salani S, Rizzo F, Nardini M, Riboldi G, Magri F, Zanetta C, Faravelli I, Bresolin N, Comi GP (2012) Direct reprogramming of human astrocytes into neural stem cells and neurons. Exp Cell Res 318:1528-1541.
Dahan P, Martinez Gala J, Delmas C, Monferran S, Malric L, Zentkowski D, Lubrano V, Toulas C, Cohen-Jonathan Moyal E, Lemarie A (2014) Ionizing radiations sustain glioblastoma cell dedifferentiation to a stem-like phenotype through survivin: possible involvement in radioresistance. Cell Death Dis 5:e1543.
Dufour C, Cadusseau J, Varlet P, Surena AL, de Faria GP, Dias-Morais A, Auger N, Léonard N, Daudigeos E, Dantas-Barbosa C, Grill J, Lazar V, Dessen P, Vassal G, Prevot V, Sharif A, Chneiweiss H, Junier MP (2009) Astrocytes reverted to a neural progenitor-like state with transforming growth factor alpha are sensitized to cancerous transformation. Stem Cells 27:2373-2382.
Eriksson PS, Perfilieva E, Björk-Eriksson T, Alborn A-M, Nordborg C, Peterson DA, Gage FH (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313.
Ernst A, Alkass K, Bernard S, Salehpour M, Perl S, Tisdale J, Possnert G, Druid H, Frisén J (2014) Neurogenesis in the striatum of the adult human brain. Cell 156:1072-1083.
Feng GD, He BR, Lu F, Liu LH, Zhang L, Chen B, He ZP, Hao DJ, Yang H (2014) Fibroblast growth factor 4 is required but not sufficient for the astrocyte dedifferentiation. Mol Neurobiol 50:997-1012.
Friedmann-Morvinski D, Bushong EA, Ke E, Soda Y, Marumoto T, Singer O, Ellisman MH, Verma IM (2012) Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science 338:1080-1084.
Gabel S, Koncina E, Dorban G, Heurtaux T, Birck C, Glaab E, Michelucci A, Heuschling P, Grandbarbe L (2016) Inflammation promotes a conversion of astrocytes into neural progenitor cells via NF-κB activation. Mol Neurobiol 53:5041-5055.
Gage FH (2002) Neurogenesis in the adult brain. J Neurosci 22:612-613.
Gaughwin PM, Caldwell MA, Anderson JM, Schwiening CJ, Fawcett JW, Compston DA, Chandran S (2006) Astrocytes promote neurogenesis from oligodendrocyte precursor cells. Eur J Neurosci 23:945-956.
Ghasemi-Kasman M, Hajikaram M, Baharvand H, Javan M (2015) MicroRNA-mediated in vitro and in vivo direct conversion of astrocytes to neuroblasts. PLoS One 10:e0127878.
Ghashghaei HT, Weimer JM, Schmid RS, Yokota Y, McCarthy KD, Popko B, Anton ES (2007) Reinduction of ErbB2 in astrocytes promotes radial glial progenitor identity in adult cerebral cortex. Genes Dev 21:3258-3271.
Götz M, Sirko S, Beckers J, Irmler M (2015) Reactive astrocytes as neural stem or progenitor cells: In vivo lineage, In vitro potential, and Genome-wide expression analysis. Glia 63:1452-1468.
Griffiths BB, Ouyang YB, Xu L, Sun X, Giffard RG, Stary CM (2019) Post-injury inhibition of miR-181a promotes restoration of hippocampal CA1 neurons after transient forebrain ischemia in rats. eNeuro doi: 10.1523/ENEURO.0002-19.2019.
Grinspan JB, Reeves MF, Coulaloglou MJ, Nathanson D, Pleasure D (1996) Re-entry into the cell cycle is required for bFGF-induced oligodendroglial dedifferentiation and survival. J Neurosci Res 46:456-464.
Guo Z, Zhang L, Wu Z, Chen Y, Wang F, Chen G (2014) In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model. Cell Stem Cell 14:188-202.
Heinrich C, Blum R, Gascón S, Masserdotti G, Tripathi P, Sánchez R, Tiedt S, Schroeder T, Götz M, Berninger B (2010) Directing astroglia from the cerebral cortex into subtype specific functional neurons. PloS Biol 8:e1000373.
Hirabayashi Y, Suzki N, Tsuboi M, Endo TA, Toyoda T, Shinga J, Koseki H, Vidal M, Gotoh Y (2009) Polycomb limits the neurogenic competence of neural precursor cells to promote astrogenic fate transition. Neuron 63:600-613.
Hunter KE, Hatten ME (1995) Radial glial cell transformation to astrocytes is bidirectional: regulation by a diffusible factor in embryonic forebrain. Proc Natl Acad Sci U S A 92:2061-2065.
Imayoshi I, Sakamoto M, Ohtsuka T, Takao K, Miyakawa T, Yamaguchi M, Mori K, Ikeda T, Itohara S, Kageyama R (2008) Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nat Neurosci 11:1153-1161.
Jessberger S, Zhao C, Toni N, Clemenson GD, Li Y, Gage FH (2007) Seizure-associated, aberrant neurogenesis in adult rats characterized with retrovirus-mediated cell labeling. J Neurosci 27:9400-9407.
Kokoeva MV, Yin H, Flier JS (2005) Neurogenesis in the hypothalamus of adult mice: Potential role in energy balance. Science 310:679-683.
Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T (2002) Identification of tissue-specific microRNAs from mouse. Curr Biol 12:735-739.
Leavitt BR, Hernit-Grant CS, Macklis JD (1999) Mature astrocytes transform into transitional radial glia within adult mouse neocortex that supports directed migration of transplanted immature neurons. Exp Neurol 157:43-57.
Lei W, Li W, Ge L, Chen G (2019) Non-engineered and engineered adult neurogenesis in mammalian brains. Front Neurosci 13:131.
Li L, Clevers H (2010) Coexistence of quiescent and active adult stem cells in mammals. Science 327:542-545.
Li L, Stary CM (2016) Targeting glial mitochondrial function for protection from cerebral ischemia: Relevance, mechanisms, and the role of microRNAs. Oxid Med Cell Longev 2016:6032306.
Liddelow SA, Sofroniew MV (2019) Astrocytes usurp neurons as a disease focus. Nat Neurosci 22:512.
Lim DA, Alvarez-Buylla A (1999) Interaction between astrocytes and adult subventricular zone precursors stimulates neurogenesis. Proc Natl Acad Sci U S A 96:7526-7531.
Lu D, Mahmood A, Qu C, Goussev A, Schallert T, Chopp M (2005) Erythropoietin enhances neurogenesis and restores spatial memory in rats after traumatic brain injury. J Neurotrauma 22:1011-1017.
Magavi SS, Leavitt BR, Macklis JD (2000) Induction of neurogenesis in the neocortex of adult mice. Nature 405:951-955.
Magnusson JP, Göritz C, Tatarishvili J, Dias DO, Smith EMK, Lindvall O, Kokaia Z, Frisén J (2014) A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse. Science 346:237-241.
Masserdotti G, Gillotin S, Sutor B, Drechsel D, Irmler M, Jørgensen HF, Sass S, Theis FJ, Beckers J, Berninger B (2015) Transcriptional mechanisms of proneural factors and REST in regulating neuronal reprogramming of astrocytes. Cell Stem Cell 17:74-88.
Michelucci A, Bithell A, Burney MJ, Johnston CE, Wong KY, Teng SW, Desai J, Gumbleton N, Anderson G, Stanton LW, Williams BP, Buckley NJ (2016) The neurogenic potential of astrocytes is regulated by inflammatory signals. Mol Neurobiol 53:3724-3739.
Moon JH, Yoon BS, Kim B, Park G, Jung HY, Maeng I, Jun EK, Yoo SJ, Kim A, Oh S, Whang KY, Kim H, Kim DW, Kim KD, You S (2008) Induction of neural stem cell-like cells (NSCLCs) from mouse astrocytes by Bmi1. Biochem Biophys Res Commun 371:267-272.
Moreno-Jiménez EP, Flor-García M, Terreros-Roncal J, Rábano A, Cafini F, Pallas-Bazarra N, Ávila J, Llorens-Martín M (2019) Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat Med 25:554.
Mori T, Buffo A, Götz M (2005) The novel roles of glial cells revisited: the contribution of radial glia and astrocytes to neurogenesis. Curr Top Dev Biol 69:67-99.
Nakano-Kobayashi A, Awaya T, Kii I, Sumida Y, Okuno Y, Yoshida S, Sumida T, Inoue H, Hosoya T, Hagiwara M (2017) Prenatal neurogenesis induction therapy normalizes brain structure and function in Down syndrome mice. Proc Natl Acad Sci U S A 114:10268-10273.
Niu W, Zang T, Zou Y, Fang S, Smith DK, Bachoo R, Zhang CL (2013) In vivo reprogramming of astrocytes to neuroblasts in the adult brain. Nat Cell Biol 15:1164-1175.
Niv F, Keiner S, Krishna -, Witte OW, Lie DC, Redecker C (2012) Aberrant neurogenesis after stroke: a retroviral cell labeling study. Stroke 43:2468-2475.
Oppenheim RW (2019) Adult hippocampal neurogenesis in mammals (and humans): The death of a central dogma in neuroscience and its replacement by a new dogma. Dev Neurobiol 79:268-280.
Palmer TD, Takahashi J, Gage FH (1997) The adult rat hippocampus contains primordial neural stem cells. Mol Cell Neurosci 8:389-404.
Paredes MF, Sorrells SF, Garcia-Verdugo JM, Alvarez-Buylla A (2016) Brain size and limits to adult neurogenesis. J Comp Neurol 524:646-664.
Perera TD, Dwork AJ, Keegan KA, Thirumangalakudi L, Lipira CM, Joyce N, Lange C, Higley JD, Rosoklija G, Hen R, Sackeim HA, Coplan JD (2011) Necessity of hippocampal neurogenesis for the therapeutic action of antidepressants in adult nonhuman primates. PLoS One 6:e17600.
Richards LJ, Kilpatrick TJ, Bartlett PF (1992) De novo generation of neuronal cells from the adult mouse brain. Proc Natl Acad Sci U S A 89:8591-8595.
Rivetti di Val Cervo P, Romanov RA, Spigolon G, Masini D, Martín-Montañez E, Toledo EM, La Manno G, Feyder M, Pifl C, Ng YH, Sánchez SP, Linnarsson S, Wernig M, Harkany T, Fisone G, Arenas E (2017) Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson’s disease model. Nat Biotechnol 35:444-452.
Robel S, Berninger B, Götz M (2011) The stem cell potential of glia: lessons from reactive gliosis. Nat Rev Neurosci 12:88-104.
Robinson C, Apgar C, Shapiro LA (2016) Astrocyte hypertrophy contributes to aberrant neurogenesis after traumatic brain injury. Neural Plast 2016:1347987.
Ruiz S, Brennand K, Panopoulos AD, Herrerías A, Gage FH, Izpisua-Belmonte JC (2010) High-efficient generation of induced pluripotent stem cells from human astrocytes. PLoS One 5:e15526.
Seri B, García-Verdugo JM, McEwen BS, Alvarez-Buylla A (2001) Astrocytes give rise to new neurons in the adult mammalian hippocampus. J Neurosci 21:7153-7160.
Sher F, Boddeke E, Copray S (2010) Ezh2 expression in astrocytes induces their dedifferentiation toward neural stem cells. Cell Reprogram 13:1-6.
Shimada IS, LeComte MD, Granger JC, Quinlan NJ, Spees JL (2012) Self-renewal and differentiation of reactive astrocyte-derived neural stem/progenitor cells isolated from the cortical peri-infarct area after stroke. J Neurosci 32:7926-7940.
Simon C, Götz M, Dimou L (2011) Progenitors in the adult cerebral cortex: Cell cycle properties and regulation by physiological stimuli and injury. Glia 59:869-881.
Sirko S, Behrendt G, Johansson PA, Tripathi P, Costa M, Bek S, Heinrich C, Tiedt S, Colak D, Dichgans M, Fischer IR, Plesnila N, Staufenbiel M, Haass C, Snapyan M, Saghatelyan A, Tsai LH, Fischer A, Grobe K, Dimou L, et al. (2013) Reactive glia in the injured brain acquire stem cell properties in response to sonic hedgehog. Cell Stem Cell 12:426-439.
Slomiany P, Baker T, Elliott ER, Grossel MJ (2006) Changes in motility, gene expression and actin dynamics: Cdk6-induced cytoskeletal changes associated with differentiation in mouse astrocytes. J Cell Biochem 99:635-646.
Song H, Stevens CF, Gage FH (2002) Astroglia induce neurogenesis from adult neural stem cells. Nature 417:39.
Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, James D, Mayer S, Chang J, Auguste KI, Chang EF, Gutierrez AJ, Kriegstein AR, Mathern GW, Oldham MC, Huang EJ, Garcia-Verdugo JM, Yang Z, Alvarez-Buylla A (2018) Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555:377-381.
Stappert L, Klaus F, Brüstle O (2018) MicroRNAs engage in complex circuits regulating adult neurogenesis. Front Neurosci 12:707.
Su Z, Niu W, Liu ML, Zou Y, Zhang CL (2014) In vivo conversion of astrocytes to neurons in the injured adult spinal cord. Nat Commun 5:3338.
Sugawara T, Kawase M, Lewén A, Noshita N, Gasche Y, Fujimura M, Chan PH (2000) Effect of hypotension severity on hippocampal CA1 neurons in a rat global ischemia model. Brain Res 877:281-287.
Tian C, Wang Y, Sun L, Ma K, Zheng JC (2011) Reprogrammed mouse astrocytes retain a “memory” of tissue origin and possess more tendencies for neuronal differentiation than reprogrammed mouse embryonic fibroblasts. Protein Cell 2:128-140.
Vallières L, Campbell IL, Gage FH, Sawchenko PE (2002) Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci 22:486-492.
Xu C, Zhang Y, Zheng H, Loh HH, Law PY (2014) Morphine modulates mouse hippocampal progenitor cell lineages by upregulating miR-181a level. Stem Cells 32:2961-2972.
Yagi S, Galea LAM (2019) Sex differences in hippocampal cognition and neurogenesis. Neuropsychopharmacology 44:200-213.
Yang H, Cheng XP, Li JW, Yao Q, Ju G (2009) De-differentiation response of cultured astrocytes to injury induced by scratch or conditioned culture medium of scratch-insulted astrocytes. Cell Mol Neurobiol 29:455-473.
Yang H, Ling W, Vitale A, Olivera C, Min Y, You S (2011) ErbB2 activation contributes to de-differentiation of astrocytes into radial glial cells following induction of scratch-insulted astrocyte conditioned medium. Neurochem Int 59:1010-1018.
Yang H, Liu C, Fan H, Chen B, Huang D, Zhang L, Zhang Q, An J, Zhao J, Wang Y, Hao D (2019) Sonic hedgehog effectively improves Oct4-mediated reprogramming of astrocytes into neural stem cells. Mol Ther 27:1467-1482.
Yang Z, Covey MV, Bitel CL, Ni L, Jonakait GM, Levison SW (2007) Sustained neocortical neurogenesis after neonatal hypoxic/ischemic injury. Ann Neurol 61:199-208.
Yasui DH, Xu H, Dunaway KW, Lasalle JM, Jin LW, Maezawa I (2013) MeCP2 modulates gene expression pathways in astrocytes. Mol Autism 4:3.
Yokoyama A, Yang L, Itoh S, Mori K, Tanaka J (2004) Microglia, a potential source of neurons, astrocytes, and oligodendrocytes. Glia 45:96-104.
Yu T, Cao G, Feng L (2006) Low temperature induced de-differentiation of astrocytes. J Cell Biochem 99:1096-1107.
Zeisel A, Muñoz-Manchado AB, Codeluppi S, Lönnerberg P, Manno GL, Juréus A, Marques S, Munguba H, He L, Betsholtz C, Rolny C, Castelo-Branco G, Hjerling-Leffler J, Linnarsson S (2015) Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science 347:1138-1142.
Zhang L, Yin JC, Yeh H, Ma NX, Lee G, Chen XA, Wang Y, Lin L, Chen L, Jin P, Wu GY, Chen G (2015) Small molecules efficiently reprogram human astroglial cells into functional neurons. Cell Stem Cell 17:735-747.
Zhang RL, Chopp M, Gregg SR, Toh Y, Roberts C, LeTourneau Y, Buller B, Jia L, Davarani SPN, Zhang ZG (2009) Patterns and dynamics of subventricular zone neuroblast migration in the ischemic striatum of the adult mouse. J Cereb Blood Flow Metab 29:1240-1250.
Zhao C, Sun G, Li S, Lang MF, Yang S, Li W, Shi Y (2010) MicroRNA let-7b regulates neural stem cell proliferation and differentiation by targeting nuclear receptor TLX signaling. Proc Natl Acad Sci U S A 107:1876-1881.
Zhao C, Sun G, Li S, Shi Y (2009) A feedback regulatory loop involving microRNA-9 and nuclear receptor TLX in neural stem cell fate determination. Nat Struct Mol Biol 16:365-371.
P-Reviewers: Ishii T, Bernstein HG, Davis RL, Fernandez-Vega I; C-Editors: Zhao M, Li JY; T-Editor: Jia Y
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