In the past decades, research related to the development of neuroprotective drugs has quickly advanced and highlighted several valuable targets to promote the relief of cognitive symptoms presented in neurodegenerative diseases. However, most drugs currently studies have limited action on the full recovery of neural tissue after lesions, which restrains their efficacy in treating neurological disorders [1].

One important therapeutic strategy that has shown promise for recovering damaged neural tissue by promoting the proliferation of new cells and further restoring brain functionality is the stem cell therapy. Thereby neural stem cells (NSCs) are the most widely used multipotent cell in neuroregenerative medicine research, mostly due to their strong potential for secreting neurotrophic substances, which can improve tissue healing by altering the microenvironment [2], [3], [4].

NSCs generate neuronal and glial progenitor cells that differentiate into neurons, astrocytes, and oligodendrocytes [5], [6]. Interestingly, preliminary results using stem cell therapy with NSCs on different animal models of neurodegenerative diseases have shown that this strategy promotes neuroregeneration and can be helpful for the recovery of neuronal viability after brain lesion, mainly by the enhancement of post-lesion neurogenesis [7], [8].

It is important to know that neurogenesis is the generation of neuronal cells that most intensely occurs during embryonic development, although it can be observed postnatally to a lesser extent. Whereas embryonic neurogenesis is responsible for the organization of brain structure and the nervous system development, adult neurogenesis is associated with regional neuronal regeneration and cognitive processes such as those related to memory and emotional regulation [9], [10]. In addition, both early and adult neurogenesis relies on several signaling pathways, and changes in the microenvironment related to these pathways' activity can positively or negatively influence this process [11].

The enhancement of post-lesion neurogenesis is one of the most promising targets for stem cell treatment in a neurodegenerative context. It is essential to deepen our knowledge of how different signaling pathways, growth, and transcription factors (TF), as well as extracellular matrix (ECM) components modulate this process. This knowledge is critical for using these tools in biotechnological applications in vivo and in vitro research and to improve the translational research progress. Hence, the present work will focus on the contribution of microRNAs, transcription factors, and ECM components to the modulation of stem cell-derived neurogenesis and how to apply them as biotechnological therapy. (Fig. 1, Fig. 2, Fig. 3).

The NSCs in the embryonic neural tube converge and concentrate in the ventricular zone during early neurogenesis. Different signaling pathways, such as the sonic hedgehog (SHH), bone morphogenetic protein (BMP), Wnt/β-Catenin, and Notch, regulates the auto-renewal of NSCs and maintain the progeny during all the embryogenic process [12], [13], [14], [15]. One crucial aspect that differentiates embryogenic from adult neurogenesis is that the former is highly orchestrated and has a markedly paralleled progression, whereas the latter occurs at any time.

There are two crucial proliferative zones during embryonic neurogenesis: the ventricular zone (VZ) and the subventricular zone (SVZ). It is known that NSCs located at the VZ of the neural tube divide symmetrically and asymmetrically to generate progenitor cells, which then migrate to SVZ and enter the differentiation process. This latter area is thought to function as a regulator of the differentiation of late-born neurons and ultimately constructs the neocortex [16], [17].

Early neurogenesis initiation is triggered by proneural genes that encode basic Helix-loop-helix (bHLH) transcription factors. They are responsible for orchestrating neuronal lineage specification and commitment of neural progenitors to neuronal differentiation through the downstream activation of pro-differentiation genes. Once the neuronal progenitors are committed, they go through neuronal differentiation and migrate farther from the ventricular zone, giving rise to mature neurons [18], [19].

After brain development, NSCs present at the SVZ and the dentate gyrus (DG) of the hippocampus maintain their ability to self-renewal and proliferation, thus giving rise to adult neurogenesis. Adult neurogenesis is observed in the SVZ of the rodent brain, where newly born neurons migrate to forebrain regions such as the olfactory bulb circuitry. Moreover, in the human brain, this neurogenic niche is thought to contribute to the generation of new neurons in the striatum, the dentate gyrus-derived generation of newborn granule cells promotes the integration of these neurons into the hippocampus, conferring enhanced neuroplasticity, which is crucial to memory and learning processes [20].

Approximately six different cell stages encompass the adult neurogenesis of granule neurons: type-1 cells, type-2a cells, type-2b cells, type 3 cells, immature, and mature neurons [11]. In the first stages, NSCs (defined as type-1 cells) produce intermediate progenitors (type-2a cells). After that, changes in the microenvironment correlated with the expression of different transcription factors turn type2-a cells into type-2b cells, producing migratory neuroblasts (classified as type-3 cells) that exit the cell cycle and enter early neuronal development. Finally, these immature neurons pass through the maturation process that changes the expression of several proteins and receptors, which helps the integration of this mature neuron into the established circuitry [21], [22], [23].

Several biomarkers expressed at this multistep progression of adult neurogenesis have been identified. The most common stem cell markers detected in the first stage, when type-1 cell proliferation occurs, are glial fibrillary acidic protein (GFAP), Nestin, and SOX2. Following, doublecortin (DCX) and polysialylated neural cell adhesion molecule (PSA-NCAM) are widely expressed throughout the early differentiation phase that includes the production of type 2 cells. At the stage characterized by the generation of type-3 cells, both DCX and PSA-NCAM can be found to a lesser extent, whereas other markers such as Tuj-1b and NeuroD are highly expressed. Moreover, the maturation process that turns immature neurons into fully integrated mature neurons gives rise to the expression of markers such as the neuron-specific nuclear protein (NeuN) and the calcium-binding protein Calbindin [21], [24].