Despite the intense research on adult neural stem cell biology suggested possible
translational outcomes in regenerative medicine for neurodegenerative diseases, neuroregeneration
is unlikely to occur in adult brain, due to intrinsic features that characterize the
neural stem cell niche.
Mesenchymal stem cells (MSCs), osteogenic stem cells residing in the bone marrow stroma
(also named bone marrow stromal cells), have been long considered highly plastic multipotent
precursors, able to commit toward diversified lineages, including non-mesodermal ones.
Their in vitro plasticity and ease of processing prompted their wide, sometimes untimely,
exploitation in diversified regenerative medicine applications (Park et al., 2012;
Bianco et al., 2013). They have been tested also for their putative, yet widely debated,
neuroregenerative potential. This controversial issue stimulated this Research Topic,
which aims to delve into relevant scientific milestones addressing the differences,
possible interconnections, and overlaps between the osteogenic and the neurogenic
niches' biology.
The debated neuronal transdifferentiation potential of MSCs recently led to their
inappropriate exploitation for the treatment of neurodegenerative disorders. The regulatory
and ethical issues regarding this topic have been discussed in the Opinion paper by
Solarino et al., delving into a recent Italian case of medical malpractice, which
triggered significant international dispute (Abbott, 2013; Blasimme and Rial-Sebbag,
2013). Indeed, a better clarification of the specific features displayed by the osteogenic
and the neurogenic stem cell niches is needed, as discussed by Lattanzi et al. This
mini-review provides a pairwise comparison of the two niches within their in vivo
environments, highlighting functionally relevant similarities and differences that
should be considered to achieve a more rational clinical translation.
The contribution by Salgado et al. provides an exhaustive description of osteogenic
and neural stem cells' features, focusing on their possible interaction within the
brain environment. In particular, the MSCs' secretome is known to exert autocrine
and paracrine effects that may be relevant for potential therapeutic exploitations,
also in the central nervous system (Ribeiro et al., 2011; Drago et al., 2013; Kim
et al., 2013; Sart et al., 2014; Wright et al., 2014).
The role of neural crest stem cells (NCSCs) in regulating the bone marrow niche is
provided in the review by Coste et al. NCSCs are capable of epithelial-to-mesenchymal
transition, and ultimately give rise to both neural precursors and nestin-positive
MSCs, actively involved in the homeostatic regulation of the hematopoietic stem cell
niche (Achilleos and Trainor, 2012; Mayor and Theveneau, 2013).
A significant overlap between the two niches relies on the molecular (Wnt, NOTCH,
FGF, TGF-BMP, SHH signaling pathways) and secretome (BDNF, NGF, VEGF, PDGF) profiles,
along with the intimate relationship with vessels, being a common structural feature
observed in adult stem cell niches.
Diverse phylogenetically old signaling pathways, including nucleotides and neuropeptides,
are shared between the osteogenic and the neurogenic niches, exerting trophic, and
immunomodulatory functions. Cavaliere et al. exhaustively discussed the often opposing
roles played by purinergic ligands. These establish a common paracrine pathway that
modulates MSCs' and NSCs' activity, in both physiological and pathological conditions.
They appear to be involved in the crosstalk between the two niches, by modulating
the immune response, which triggers stem cell recruitment after stressful insults
(Cavaliere et al.).
Among neuropeptides, the direct effects of neuropeptide Y (NPY), mediator for signaling
in both neurogenic and osteogenic niches, has been reviewed by Geloso et al., with
special attention to its effects on neurogenic niche. Data indicating a direct pro-neurogenic
effect of NPY on NSCs, as well as the concomitant modulatory action on astrocytes,
microglia, and endothelium activities within the niche have been discussed. Interestingly,
a possible crosstalk between released nucleotides and NPY related pathways emerges
(Jia and Hegg, 2012), suggesting that they could also represent a point of intersection
between shared ancient molecular pathways.
Neurotransmitters released by the sympathetic nervous system, interestingly including
NPY, as recently reviewed by Park et al. (2015), are known to be also involved in
the regulation of hematopoietic stem cell (HSC) functions, mainly acting on endothelial
cells and nestin-positive MSCs, which retain HSCs. In this regard, the relevance of
catecholaminergic modulation of hematopoiesis has been extensively reviewed by Cosentino
and coworkers (Cosentino et al.), highlighting their established role in the complex
network of neural and neuroendocrine agents that regulate stem cell biology (Cosentino
et al.).
Within the wide range of external stimuli acting on the epigenetic control of adult
tissue stem cell niches, the effects of extremely-low frequency electromagnetic field
(ELFEF) stimulation is emerging as a tool to modulate neurogenic and osteogenic processes,
as discussed by Leone et al. They highlighted the possible shared pathways induced
by ELFEFS on both niches, including Wnt/beta-catenin signaling and the activation
of p300 or other histone acetyltransferases by Runx2 (Leone et al.).
The interdependence of brain and skull during development seems to rely also on the
role of interposed meninges (Richtsmeier and Flaherty, 2013). Within this intriguing
topic, Bifari et al. provided findings showing the distribution of neural precursor
markers in rat meninges during development up to adulthood, related to the newly identified
niche function of meninges (Decimo et al., 2011).
Finally, an interesting evolutionary perspective on the relation between osteogenesis
and neurogenesis is provided in the opinion paper by Boeckx and Benítez-Burraco, who
approached this topic from a different “biolinguistic” standpoint. The Authors postulated
that critical genes active in the osteogenic niche (including homeogenes, e.g. DLXs,
morphogens, e.g. BMPs, and the master regulatory RUNX2 gene), hence giving rise to
skull globularity in anatomically modern humans, also have important consequences
in brain development and plasticity, ultimately leading to our distinctive mode of
cognition (Boeckx and Benítez-Burraco).
Taken together, the papers included in this research topic seem to suggest an emerging
cross-domain scenario in which significant molecular signaling and biological features
are shared between osteogenic and neurogenic stem cells niches. The two niches appear
to be interconnected in evolution, during development, and further beyond. Nonetheless,
relevant differences in the relative stem cell niche dynamics should not be neglected,
in order to appropriately design potential cross-lineage tissue regenerative strategies.
Author contributions
Both Authors contributed equally in conceiving, drafting, revising, and finalizing
the present manuscript.
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.