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Bioinformatics of the Brain

Ease of isolation protocols, alternative delivery routes, safety in trans-

planted individuals, and all these fantastic biological features above have made

human MSCs and MSC-derived EVs are indispensable in cell-based therapeu-

tic approaches for over 30 years since they were isolated in 1992 for the first

time [11, 12]. For this reason, it is currently possible to come across 1621 clin-

ical studies for the treatment of a broad range of diseases when searching for

the keyword mesenchymal stem cells in the NIH Clinical Trials database (clin-

ical.gov). Diabetic nephropathy, bronchopulmonary dysplasia, hemophilia, re-

tinitis pigmentosa, cystic fibrosis, mandibular fractures, cardiomyopathies, di-

abetes mellitus, hypoxic-ischemic encephalopathy, tracheal stenosis, tendon

injuries, anemias, spinal cord injury, stroke, osteoarthritis, rheumatoid arthri-

tis, knee osteoarthritis, lupus erythematosus, cerebellar ataxia, hyposalivation,

gingival recession, pneumoconiosis, cancers, Duchenne muscular dystrophy,

and post-acute COVID-19 syndrome are just a minority of the samples in

which MSCs have expediently been in service (clinical.gov).

2.2.2.2

Neural Stem Cells (NSCs) and Neurogenesis

Neurogenesis, first proposed by Joseph Altman in 1962 [13], is a crucial pro-

cess leading to the production of nerve cells, or neurons, from neural stem cells

(NSCs). Neural stem cells and neural progenitors exist in specific niches, the

subventricular zone (SVZ) and the subgranular zone (SGZ), within the adult

mammalian central nervous system (CNS), to provide lifelong brain plastic-

ity [14]. NSCs are biologically more active during embryonic development;

however, NSCs in adults are usually in a quiescence state [15]. Upon neural

inductions, neurogenesis is triggered to allow terminal differentiation of sorts

of neurons and glial cells. NSC niches in adult brains supply molecular signals,

including small ligands, growth factors, systemic hormones, neurocytokines,

neurotransmitters (GABA, dopamine, etc.), ECM components, and cell junc-

tion molecules, to contribute to NSC differentiation, or neurogenesis [16].

In adults, once quiescent NSCs, namely radial glia-like (RGL) cells (Type

I cells) in SGZ, are activated through intrinsic and extrinsic regulators, they

start to divide and generate a cell population of intermediate proliferating

progenitors (IPCs). IPCs continue their differentiation course by composing

neuroblasts. Neuroblasts

can migrate towards certain regions of the CNS

and transform into immature neurons. Finally, dentate granule cells are de-

rived and located within the dentate gyrus in the hippocampus. On the other

hand, RGL-neural stem cells (Type B cells) in SVZ first commit to transient

amplifying progenitors (C cells). After dividing for multiple rounds, C cells

differentiate into neuroblasts. Type B cell-derived neuroblasts then move to

the olfactory bulb, where they give rise to various types of interneurons in the

CNS [14, 16, 17]. Activated RGL cells (aRGL) also derive into glial cells, in-

cluding astrocytes, oligodendrocytes, and ependymal cells in the human CNS

[18]. Neurological diseases are essentially caused by either diminished neuronal

differentiation, or the unexact functioning of the neurons. In conclusion, NSCs

indispensably ensure a healthy brain by sustaining normal development and