Cell and Tissue Research (2018) 371:1–6

https://doi.org/10.1007/s00441-017-2738-1

EDITORIAL

Neural stem cells: developmental mechanisms and disease modeling

Xinyu Zhao 1,2 & Darcie L. Moore 1

Published online: 2 December 2017

# Springer-Verlag GmbH Germany, part of Springer Nature 2017

Summary Stem cells

The astonishing progress in the field of stem cell biology The term Bstem cells^ first appeared in the scientific literature
during the past 40 years has transformed both science and in 1868 by the German biologist Ernst Haeckel (Haeckel
medicine. Neural stem cells (NSCs) are the stem cells of 1868). In his writings (Haeckel 1868), Bstem cells^ had two
the nervous system. During development they give rise to distinct meanings: one is the unicellular evolutionary origin of
the entire nervous system. In adults, a small number of all multicellular organisms and the other is the fertilized egg
NSCs remain and are mostly quiescent; however, ample giving rise to all other cell types of the body. The latter defi-
evidence supports their important roles in plasticity, ag- nition has evolved into the modern definition of stem cells—
ing, disease and regeneration of the nervous system. cells that can divide to self-renew and to differentiate into
Because NSCs are regulated by both intrinsic genetic other cell types in tissues and organs (Li and Zhao 2008;
and epigenetic programs and extrinsic stimuli transduced Ramalho-Santos and Willenbring 2007).
through the stem cell niche, dysregulation of NSCs due to The behavior and fate of stem cells are strongly influenced
either genetic causes or environmental impacts may lead by their specific anatomical locations and surrounding cell
to disease. Therefore, extensive investigations in the past types, called “the stem cell niche.” The niche provides phys-
decades have been devoted to understanding how NSCs ical support to host or anchor stem cells and supplies factors to
are regulated. On the other hand, ever since their discov- maintain and regulate them (Li and Zhao 2008). Stem cells are
ery, NSCs have been a focal point for cell-based therapeu- also regulated by intrinsic signaling cascades and transcrip-
tic strategies in the brain and spinal cord. The limited tional mechanisms, some of which are common among all
number of NSCs residing in the tissue has been a limiting stem cells and others that are unique to specific types. Some
factor for their clinical applications. Although recent ad- of the best known regulators include TGF-β, BMP, Smad,
vancements in embryonic and induced pluripotent stem Wnt, Notch and EGF fibroblast growth factors (Jobe et al.
cells have provided novel sources for NSCs, several chal- 2012; Li and Zhao 2008). Therefore, stem cells are regulated
lenges remain. In this special issue, leaders and experts in by complex mechanisms in both temporal- and context-
NSCs summarize our current understanding of NSC mo- specific manners to maintain their unique characteristics.
lecular regulation and the importance of NSCs for disease Understanding stem cell regulation gives us the opportunity
modeling and translational applications. to explore mechanisms of development, as well as disorders
resulting from their dysfunction.

* Xinyu Zhao NSCs in development

[email protected]
During development, the central nervous system (CNS) is
Darcie L. Moore generated from a small number of neural stem cells (NSCs)
[email protected]
lining the neural tube (Kriegstein and Alvarez-Buylla 2009).
1
Department of Neuroscience, Waisman Center and University of A great deal of experimental evidence has demonstrated that
Wisconsin-Madison, Madison, WI 53705, USA radial glia, the NSCs during mammalian CNS development,
2
Waisman Center and University of Wisconsin-Madison, undergo both symmetric divisions to expand the NSC pool
Madison, WI 53705, USA and asymmetric divisions to give rise to intermediate
2 Cell Tissue Res (2018) 371:1–6

progenitors (IPCs) and the differentiated cell types. The three behaviors such as pattern separation (Aimone et al. 2011)
major cell types in the CNS arise from NSCs in a temporally and spatial learning (Dupret et al. 2008), as well as
defined sequence, with neurons appearing first, followed by hippocampus-associated learning, memory and executive
astrocytes and then oligodendrocytes (Okano and Temple functions (Kempermann et al. 2015).
2009). The technical advancement of live imaging and geno- Significant effort has been devoted into understanding the
mic tools have allowed for the identification of human- regulation of adult neurogenesis. As a result, we now know
specific NSC populations (e.g., outer radial glia, or oRG) lo- that many extrinsic stimuli and intrinsic mechanisms can af-
cated at the outer subventricular zone (SVZ) (Gertz et al. fect this process. Mouse genetic studies have clearly demon-
2014). These oRG are essential for cortical expansion to strated the important role of transcriptional regulation of
achieve the large size of the human cortex. Single-cell geno- NSCs through intrinsic genetic mechanisms (Hsieh and
mic technologies have identified specific oRG markers that Zhao 2016). Some examples include SOXC family proteins
might be used for further characterization of these cells (Liu (Kavyanifar et al. 2018, in this issue), Bmi-1 (Molofsky et al.
et al. 2016, Pollen et al. 2014). Investigating the regulatory 2003), Sox2 (Ferri et al. 2004; Graham et al. 1999), PTEN
mechanisms governing the self-renewal and fate specification (Bonaguidi et al. 2011) and Notch (Zhang et al. 2018, in this
of NSCs, especially human-specific developmental features, issue). In addition, epigenetic regulation by DNA methylation
has significantly contributed to our understanding of human pathways (e.g., Mbd1, Mecp2, Dnmt, Tet) (Noguchi et al.
brain development and developmental diseases. In addition, 2015; Smrt et al. 2007; Tsujimura et al. 2009; Zhang et al.
this knowledge has also helped scientists refine protocols for 2013; Zhao et al. 2003), chromatin remodeling (e.g., BAF,
pluripotent stem cell differentiation into specific nervous sys- BRG1) (Ninkovic et al. 2013; Petrik et al. 2015; Tuoc et al.
tem cell types for both therapeutic goals and disease 2017) and noncoding RNAs (Liu et al. 2010; Anderson and
modeling. Lim 2018, in this issue) play important roles. Many growth
factors, signaling molecules and neurotransmitters have been
shown to regulate neurogenesis (Kempermann et al. 2015).
NSCs in the adult brain Catavero et al. (2018, in this issue) review the role of
GABA circuits, signaling and receptors in regulating develop-
In adult brains, NSCs are reduced and become restricted to ment of adult-born cells, as well as the molecular players that
specific brain regions. In rodents, both NSCs and ongoing modulate GABA signaling. Because progenitors with
neurogenesis have been widely documented in the SVZ of multipotent differentiation potentials have been found in brain
the lateral ventricles and the subgranular zone (SGZ) of the regions without active neurogenesis (Palmer et al. 1997), it is
dentate gyrus (DG) of the hippocampus (Kempermann et al. hypothesized that these progenitors might be manipulated to
2015). In humans, experimental evidence has supported on- become neuron-competent in vivo so that they can contribute
going neurogenesis in the hippocampus (Eriksson et al. 1998; to brain generation (Wang and Zhang 2018, in this issue).
Spalding et al. 2013). The confirmation of mammalian adult A great amount of literature has documented how physio-
neurogenesis in the 1990s was one of the most exciting mo- logical activities and an enriched environment influence adult
ments in science in the 21st century. Not only did it overthrow neurogenesis (Kempermann et al. 2015). However, as sum-
the prevailing dogma suggesting no neurons were made in the marized by Eisinger and Zhao (2018, in this issue), the genes
adult brain but it also hinted that these adult NSCs could be and gene network involved in these changes within NSCs
utilized for neural repair in disease and following injury. Forty have not been systematically analyzed at genome wide levels.
years later, we have learned a lot about NSCs. In the adult Adult neurogenesis is also influenced by diseases including
rodent SVZ, neurogenesis has been shown to be important epilepsy (Parent and Lowenstein 1997), stroke (Zhang and
for olfactory function and olfactory learning (Alonso et al. Chopp 2016), depression (Dranovsky and Hen 2006;
2006). During development, a subset of slowly-dividing Kempermann et al. 2003) and injury (Morshead and Ruddy
NSCs are set aside to be the NSCs of the SVZ in the postnatal 2018, in this issue). Thodeson et al. (2018, in this issue) fur-
and adult brain (Fuentealba et al. 2015; Furutachi et al. 2015). ther summarize the contribution and dysregulation of adult
The majority of neurogenic radial glia, however, become as- neurogenesis in epilepsy and discuss how we can translate
trocytes and ependymal cells at the end of embryonic these findings to human therapeutics by using patient-
neurogenesis (Noctor et al. 2004). A subset of these astrocytes derived neurons to study monogenic epilepsy-in-a-dish.
persist as NSCs in specialized niches in the adult brain and Aging affects every individual and is a major risk factor for
continuously generate neurons that functionally integrate into many diseases. One of the strongest negative regulators of
restricted brain regions (Doetsch 2003). In the hippocampus, adult neurogenesis is aging. Both intrinsic and extrinsic com-
radial glia-like stem cells of the SGZ make newborn neurons ponents regulate the limitations of NSC proliferation and
throughout life (Goritz and Frisen 2012). These newborn neu- function (Moore and Jessberger 2017; Seib and Martin-
rons integrate into the circuity of the DG, contributing to Villalba 2015). In this issue, Mosher and Schaffer (2018)
Cell Tissue Res (2018) 371:1–6 3

and Morshead and Ruddy (2018) examine factors such as neural differentiation protocol, most neural progenitors ob-
secreted signals, cell contact-dependent signals and extracel- tained are forebrain excitatory progenitors that produce mostly
lular matrix cues that control neurogenesis in an age- forebrain glutamatergic excitatory neurons. However, the pu-
dependent manner and define these signals by the extrinsic rity and layer-specific composition of these progenitors, as
mechanism through which they are presented to the NSCs. well as neurons, vary significantly from experiment to exper-
Smith et al. (2018, in this issue) discuss how age-related iment, cell line to cell line and lab to lab. In addition, differ-
changes in the blood, such as blood-borne factors and periph- entiation into specific types of neurons with high purity has
eral immune cells, contribute to the age-related decline in always been a challenging goal. Much effort has been devoted
adult neurogenesis in the mammalian brain. into improving the efficiency of dopaminergic neuron and
Despite the extensive knowledge we have gained regarding GABAergic neuron differentiation with great success (Hu
adult neurogenesis, critical questions remain. For example, the et al. 2010). However, the brain has many other types of neu-
control of the functional integration of new neurons remains a rons. Vadodaria et al. (2018, in this issue) discuss how to
mystery. It has been shown that adult NSC-differentiated new- generate serotonergic neurons, a type of neuron highly rele-
born neurons exhibit a critical period for sensitivity to external vant to psychiatric disorders. To better understand the molec-
stimuli (Bergami et al. 2015) and a heightened sensitivity to ular control of human PSC and NSC differentiation, where
seizures (Kron et al. 2010). It remains unclear how new neu- protocols result in a large amount of cellular heterogeneity in
rons choose their connections. Jahn and Bergami (2018, in identity and response, analysis must be done at the level of
this issue) further discuss the critical period and its regulators single cells. Harbom et al. (2018, in this issue) summarize how
during adult-newborn neuron development. new state-of-the-art single-cell analysis methods may help to
Understanding the extrinsic and intrinsic regulation of define differentiation from pluripotent cells.
adult NSCs and their newborn progeny and their response to The advancement in iPSC and gene editing technology has
both positive and negative stimuli will further illuminate their transformed the field of human disease modeling. As in many
role in disease, injury, stress and brain function. human disorders, especially neuropsychiatric disorders,
mouse models have been useful. Yet there are several critical
reasons why it is necessary to use human cells to define the
Pluripotent stem cell-derived NSCs underlying mechanisms that lead to human patient character-
istics, particularly those affecting the nervous system. For ex-
Human pluripotent stem cells (PSCs), including human em- ample, in fragile X syndrome (FXS), the epigenetic silencing
bryonic stem cells (ESCs) and induced PSCs (iPSCs), offer a of the Fragile X Mental Retardation Gene 1 (FMR1) gene that
model system to reveal cellular and molecular events causes FXS occurs only in humans. Mice engineered to mimic
underlying normal and abnormal neural development in the human mutation in the FMR1 gene do not show the same
humans. ESCs are pluripotent cells derived from the inner methylation and silencing characteristics of the gene as in
cell mass of blastocyst stage preimplantation embryos, humans (Brouwer et al. 2007). These results indicate that
which were first isolated in 1981 from mouse by Evans and some epigenetic mechanisms in human and mice are different
Kaufman (1981) and later, in 1998, from humans by Thomson and preclude the ability to study epigenetic mechanisms of
et al. (1998). Human ESCs are invaluable in the study of early FMR1 silencing in mouse models of FXS (Bhattacharyya
embryonic development, allowing us to identify critical regu- and Zhao 2016). In this issue, Li and Shi discuss disease
lators of cell commitment, differentiation and adult cell modeling using human PSC-differentiated neural progenitors
reprogramming (Dvash et al. 2006; Ren et al. 2009). iPSCs (Li et al. 2018), and Brito et al. specifically focus on modeling
are reprogrammed from somatic cells by forced expression of autism spectrum disorder (Brito et al. 2018).
stem cell genes and have the characteristics of ESCs (Okita
et al. 2007; Yu et al. 2007). The development of iPSC tech-
nology has allowed us access to cells of the human nervous Use of NSCs as therapy
system through reprogramming of patient-derived cells, revo-
lutionizing our ability to study human development and The use of NSCs as a treatment strategy in CNS disease and
diseases. injury has been tested for decades. Parkinsons’ disease specif-
To generate neural cells from either ESCs or iPSCs, the first ically has gained the most momentum for potential therapeutic
step is neural induction. Through actions of a number of acti- benefits (Studer 2017); however, similar work has been per-
vators and inhibitors of cell signaling pathways, this process formed in Huntington’s disease, stroke and following spinal
yields neural epithelial cell-like NSCs and then intermediate cord injury (for a review on this topic, see Vishwakarma et al.
neural progenitors, resembling embryonic development. 2014). In some of these paradigms, NSCs are expected to
Despite many advances, a major hurdle of neural differentia- differentiate into a specific cell type in the local CNS environ-
tion is lineage control. Using a Bstandard^ dorsal forebrain ment; in other cases, they are in a supportive role. In this issue,
4 Cell Tissue Res (2018) 371:1–6

Kameda et al. explore progress in using NSCs as a therapy Acknowledgements We thank Klaus Unsicker for his encouragement
and support and Jutta Jäger for her help with invitations and communi-
following spinal cord injury (Kameda et al. 2018).
cations with authors and reviewers. This work was supported by grants
from the US National Institutes of Health (R01MH078972,
R56MH113146, R21NS098767 and R21NS095632 to X.Z,
U54HD090256 to the Waisman Center), University of Wisconsin
Bypassing NSCs? (UW)-Madison Vilas Trust (Kellett Mid-Career Award to X.Z.) and
UW-Madison and Wisconsin Alumni Research Foundation (WARF to
While the development of PSC technologies has been a sci- X.Z.), Jenni and Kyle Professorship (to X.Zhao), a Sloan Research
Fellowship (to D.L.M.), a Junior Faculty Grant from the American
entific breakthrough for future studies, there are limitations Federation for Aging Research (to D.L.M.) and startup funds from UW-
and risks that may be associated with their use. ESCs, iPSCs Madison School of Medicine and Public Health, WARF and the
and their differentiated NSCs are dividing cells. Either trans- Neuroscience Department (to D.L.M.).
plantation of NSCs or in vivo reprogramming of endogenous
cells into NSCs could lead to tumorigenesis. In addition,
reprogramming somatic cells into iPSCs results in a loss of References
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