Two decades of intense investigation in the field of adult neurogenesis (AN) provided
us with a fully renewed vision of brain plasticity, involving stem/progenitor cells
capable of generating new neurons and glial cells throughout life. We know for sure
that new neurons produced within canonical stem cell niches do play a significant
role in cognitive tasks (learning/memory) operated by specific neural systems (Lepousez
et al., 2013; Aimone et al., 2014). The fact that neural stem/progenitor cells (NSC)
produce new elements that can integrate within some regions of the mature brain, replacing
lost neurons/glial cells or adding to pre-existent neural circuits, appears extremely
fascinating in the perspective of regenerative therapeutic approaches. Since the burst
of investigations in AN/NSC field in the nineties, many neurobiologists addressed
their studies on brain plasticity in the hope of brain repair, often discussing their
results in a translational context. Nevertheless, in spite of striking efforts to
clarify mechanisms/factors regulating AN and its physiological function, the question
whether it can be exploited for healing neurologic diseases remains unsolved. More
recent findings revealed additional examples of “non-canonical” neurogenesis and gliogenesis
in various regions of the mammalian central nervous system (CNS; reviewed in Bonfanti
and Peretto, 2011). These discoveries also open new hopes for brain repair, since
the occurrence of spontaneous neuro-gliogenesis within the parenchyma does represent
an endogenous source of progenitor cells even outside the restricted environment of
canonical neurogenic sites. Nevertheless, parenchymal cell genesis remains substantially
obscure as to its functional meaning(s) and outcome(s), and not yet exploitable for
brain repair. Such an impasse largely resides on evolutionary discrepancies: most
vertebrates use AN for brain repair as a byproduct of evolution, in addition to its
physiological functions; mammals have lost such capacity, mainly because of unfavorable
environments for repair/regeneration in their mature CNS (Bonfanti, 2011). A scarce
perception of these facts might have produced misconceptions among scientists, sometimes
leading to attitudes of unconditional optimism.
This Editorial is part of a Frontiers' research topic (and related e-book), gathering
18 articles which were intended to explore the relationships between actual existence
of NCSs in mammals (playing homeostatic roles in AN and responding to pathological
conditions) and lack of effective reparative outcome in terms of regenerative neurology.
The topic was conceived starting from a critical pragmatism but also with the strong
conviction that a promising future for AN research field is laying ahead, in the still
far, yet conceivable, perspective of developing new therapeutic strategies. In our
opinion, such hope is justified by the undeniable fact that our vision of brain structure
and function has been fully reshaped after the discovery of structural plasticity
involving NSC activity and AN outcomes. Accordingly, new dynamic, previously unsuspected
impacts on brain physiology and pathology are expectable from such knowledge.
At present, multiple issues are still open. One first, fundamental question concerns
the intrinsic limits of AN: does AN physiological functions include a role in brain
repair? Some publications exploring canonical stem cell niches, such as the olfactory
system (Oboti and Peretto, 2014; Sakamoto et al., 2014) and hippocampus (Vadodaria
and Jessberger, 2014), strongly suggest that birth, specification, migration, and
integration of young neurons is fashioned for these specific brain circuits with the
demand for a special form of plasticity in the adult brain. This picture sets limits
to the use of adult NSCs (at least for cell replacement strategies), leaving a possibility
for neuronal integration only within anatomically-restricted regions and/or during
short critical periods (Lois and Kelsch, 2014; Obernier et al., 2014; Turnley et al.,
2014; Yamaguchi and Mori, 2014).
On these bases, most papers deal with the main constraints hampering exploitation
of AN for neural cell replacement in aging and neurodegenerative diseases, including
the quiescence and regional specification of progenitors, the failure in migration
and integration of the newly born neurons. Hence, a second question could be: are
stem cells restricted in fate limiting repair of different neuronal types? The first
gap is in our understanding of quiescence vs. activity of the progenitors, and what
is needed to control their in vivo regional specification. Very little is known about
cell cycle parameters of adult neural, or any other somatic, stem cell. Some aspects
under investigation, such as the variation of cell cycle length in pathological vs.
physiological conditions, in gliogenic vs. neurogenic precursors, or in gray matter
vs. white matter, can be linked to differently long periods of quiescence followed
by re-entry in the cell cycle (Bragado Alonso et al., 2014). Also, the belief that
neuronal precursors had extensive developmental plasticity has been rediscussed. Research
during the last 20 years has shown that, in most cases, the fate of neurons is strongly
determined and that it rarely changes (Lois and Kelsch, 2014). Even within the same
lineage, the stem and progenitor cells are strikingly heterogeneous including NSCs
that are dormant or mitotically active. These differences in NSC populations and activity
states, including their role in neurogenesis and regeneration, how the different stem
cells respond to aging, and how differences in cell signaling might contribute to
adult NSC heterogeneity, are discussed by Giachino and Taylor (2014). In parallel,
NSCs in the subventricular zone cannot acquire cortical, striatal or hippocampal properties
following transplantation, rather, under normal physiological conditions they are
highly specialized and regionally specified in a cell-autonomous manner to produce
specific types of neurons destined for unique circuits within particular brain regions
(Obernier et al., 2014).
A third question is: can neuron migrate, integrate and properly survive to provide
functional repair? An important obstacle for brain repair in the adult brain is the
long distances that frequently separate endogenous germinal niches, or sites of transplantation
of progenitor cells, from the sites where new neurons would be required. Migration
through the adult brain is limited to very specific paths and to specific subtypes
of neurons and glial cells (Lois and Kelsch, 2014; Obernier et al., 2014). Neural
precursor cells can respond to neural damage by proliferating, migrating to the site
of injury, and differentiating into neuronal or glial lineages. However, after a month
or so, very few or no newborn neurons can be detected, suggesting that even though
neuroblasts are generated, they generally fail to survive as mature neurons and contribute
to the local circuitry. The article by Turnley et al. addresses this lack of survival
and integration as one of the major bottlenecks that inhibits effective neuronal replacement.
They analyze factors that enhance newborn neuron survival and integration under normal
physiological conditions, including neurotransmitters, cytoskeletal rearrangements,
neurotrophins, and other modulators of neural plasticity (see also Eiriz et al., 2014).
Other crucial and unresolved questions were addressed by our Perspective article (Peretto
and Bonfanti, 2014): comparative analyses have not yet elucidated to which extent
brain regenerative capability is a byproduct of evolution and to which extent the
knowledge of mechanisms in physiological plasticity can implement brain repair. Also,
it remains obscure how mature tissue environment can determine the outcome of AN in
neurogenic niches vs. parenchymal regions, in mammals vs. non mammalian species, and,
among mammals, in humans. Hence, defining the degree of lineage plasticity of adult
NSCs and the signals that can override their intrinsic programming has important implications
for developing cell replacement strategies based on the mobilization of endogenous
cells.
A fourth theme regards the caveats to be considered before brain repair can be achieved
from AN. Prospective solutions can fall into two domains: those trying to solve the
above mentioned pitfalls (linked to specification, migration, integration of progenitors
and their progeny, thus aiming at cell replacement) and those involving approaches
alternative to the classic view of a regenerative neurology (not aiming at cell replacement).
To solve the former problems both studies on cell autonomous properties (e.g., by
shaping the neuronal differentiation of endogenous progenitors or using reprogrammed/engineered
cells; Broccoli et al., 2014; Lois and Kelsch, 2014; Obernier et al., 2014) and environmental
permissiveness (e.g., by extending or re-opening critical periods; Yamaguchi and Mori,
2014) can be addressed. On the whole, adult-born neurons themselves may not be useful
to directly repair the brain, but learning from AN and developing new technological
tools should guide our attempts to use engineered stem cells to achieve this goal.
The alternative approaches could be linked to various functions of AN exerted in a
wider context of brain plasticity both in physiology and pathology, a concept that
is well introduced by the articles of Vadodaria and Jessberger (2014) and Butti et
al. (2014). The dual role of AN cellular plasticity vs. cellular replacement for brain
repair (remote plasticity) is analyzed by Quadrato et al. (2014). The open question
about the ultimate impact of AN in the whole brain function is an issue which gained
high interest in the last few years. The classic view of regenerative medicine aimed
at using NSCs for replacing lost elements seems very hard to be realized in the near
future for the mammalian CNS. By contrast, other functions/properties of neural progenitors
could be exploited in exploring alternative roads to “structural” brain repair. Several
articles discuss this issue under different points of view. Vadoaria and Jessberger,
and Oboti and Peretto, address the physiological role of hippocampal and olfactory
bulb neurogenesis and how it potentially contributes to the activity of different
brain circuits. Endogenous stem/progenitor cells can be exploited for enhancing cognition
in the diseased brain (Bordey, 2014). Within this context also falls the so-called
bystander effect(s), which is analyzed in detail by Butti et al. (2014).
Another issue which has been rapidly expanding during the last few years is the occurrence
in the mature CNS parenchyma of a vast population of progenitor cells still capable
of division, which mainly provide continuous gliogenesis. Two articles deal with adult
gliogenesis from NG2 cells, analyzing how these widely distributed parenchymal progenitors
can act in brain physiology and repair (Nishiyama et al., 2014), and whether their
purported role in oligodendrocytic cell replacement could be only one among other
unknown functions in brain plasticity and repair (Boda and Buffo, 2014).
A final point regards the attitude of scientists in discussing the possible (at present
non-existent) AN translational outcomes in their publications. Two levels of discussion
should be addressed, concerning the production and interpretation of results (Peretto
and Bonfanti, 2014), introducing another unanswered question: do we need adjustments
in the peer review process of AN manuscripts to deal with gaps in experimental plan
and result interpretation? A general survey of the main difficulties and pitfalls
encountered in the translation of AN basic research knowledge accumulated during the
last two decades to effective therapies for neurological diseases is also discussed
in Lois and Kelsch (2014). A further analysis of the negative impact that science
communication to the public can have on the society has been done in the Opinion paper
by Cattaneo and Bonfanti (2014).
Our general feeling, as well as our conclusion, is that a future for research in AN
have to necessarily pass through more fundamental research aimed at further understanding
of the molecular/cellular mechanisms and the evolutionary logic of such type of plasticity
before therapeutic approaches can be figured out and realized. Of course, researchers'
attitude in supporting the importance and value of basic research even in the absence
of immediate translational outcomes is fundamental in creating in patients and research
financing institutions (private and public) the awareness that complex issues such
as brain plasticity and repair in mammals cannot be addressed simply as the search
for a therapy.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.