The adult brain repairs itself after stroke by inducing neurogenesis in atypical regions such as the striatum and cortex. There is strong interest in exploiting this response for therapeutic purposes. Enhancing this self-repair process could facilitate the development of novel therapies for stroke.

Ace Therapeutics, a leading provider of stroke research services, is committed to helping clients explore the mechanisms involved in stroke-induced neurogenesis and develop strategies for stimulating ischemia-induced neurogenesis.

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Neurogenesis in the Brain after Ischemic Stroke

In ischemic stroke, neurogenesis (the production of new neurons) is stimulated in the infarcted and surrounding brain areas. They are generated by neural stem cells (NSCs) or neural progenitor cells (NPCs) from the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus of the hippocampus, which are involved in the repair and recovery of the brain after stroke.

After an ischemic injury, NPCs proliferate, differentiate, and migrate to the target to replace dead neurons. Such cells produce anti-inflammatory cytokines that help mitigate the harmful inflammatory environment, while also establishing new neuronal connections to enhance nerve function recovery and provide resistance against further ischemic damage.

In addition, after cerebral ischemic injury, many growth factors and multiple proteins are activated, and thus NSCs and NPCs can spread. This generates neurogenesis – the creation of new neurons, glial cells, axons, myelin sheaths, and synapses.

However, these newborn neurons are frequently snuffed out because there is not enough microenvironment, not enough trophic factors, and chronic inflammation. Acute neuroinflammation has been shown to support neurogenesis and possibly promote survival of neurons. Ageing still plays a role in neurogenesis, with the amount occurring slowing with age.

Fig. 1 Ischemic-induced adult neurogenesis. (Marques, et al., 2019)

Enhancing Factors of Neurogenesis

There are three phases of neurogenesis: (1) neurogenic development by neural stem cells, (2) the movement of neuroblasts and early neurons, and (3) their transformation into neurons, followed by the extension of neurites, synaptogenesis, and synapse stabilization. These phases are controlled by different molecules, and neurogenesis in the embryo and adult differs.

Growth Factors

In the CNS, neuronal survival, differentiation, and axonal renewal require growth factors including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell lineage-derived neurotrophic factor (GDNF), neurotrophin-3/4 (NT-3/4), and insulin-like growth factor 1 (IGF-1). It's their signaling pathways phospholipase C-γ (PLC-γ), phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) pathways that mediate neurogenesis in stroke.

Fig. 2 The enhancing factors of neurogenesis and their major downstream signaling pathways. (Mu, et al., 2023)

MicroRNAs

MicroRNAs (miRNAs), 20–25-nucleotide noncoding RNAs, regulate ischemic stroke and axonal growth in neurons. Major miRNAs involved in neurogenesis are miR-133b, miR-30b, miR-132, miR-124, and miR-146. These miRNAs control other biological processes by attacking several proteins and pathways.

Inhibiting Factors of Neurogenesis

Its sluggish neurogenesis in the wake of cerebral ischemia comes from the microenvironment inhibiting the regeneration of nerves: glial scarring in particular. This scarring blocks new axon development. Most of these inhibitors stimulate the RhoA/ROCK signaling system, which is responsible for many different functions within cells, such as the organization of cytoskeletons and cell migration.

Fig. 3 Inhibiting factors of neurogenesis and their major downstream signaling pathways. (Mu, et al., 2023)

Myelin Proteins

Myelin is the main barrier that inhibits neurogenesis. Some factors that inhibit axon growth such as Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp) are mainly expressed in CNS myelin.

Glial Scar

After the stroke, reactive astrocytes proliferate and contribute to the formation of a physical barrier known as the glial scar, characterized by increased expression of glial fibrillary acidic protein (GFAP) and chondroitin sulfate proteoglycans (CSPGs). CSPGs, in particular, act as inhibitors of axonal growth and plasticity, preventing regeneration after CNS injury.

Strategies for Stimulating Ischemia-Induced Neurogenesis

The main challenge for effective neurogenesis recovery is not the insufficient production of neuroblasts but improving the survival and maturation of these cells. Several strategies have been explored to promote neurogenesis after stroke.

Small Molecule Compounds

Various small molecule compounds have been developed and many growth factors have been identified to protect neural stem cells and enhance neurogenesis after stroke. Basic fibroblast growth factors, BDNF, BMP, GDNF, TGF, and NGF, play crucial roles in protecting neural stem cells and promoting neurogenesis after stroke. For example, intrastriatal infusion of GDNF increased cell proliferation in ipsilateral SVZ, and recruitment of new neuroblasts into the striatum after MCAO, and improved survival of new mature neurons.

Stem Cell-Based Therapy for Stroke

Various stem cells, including NSCs, mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs), are being studied for their potential in stroke therapy. These cells can differentiate into neurons and other neural subpopulations, and they promote neurogenesis and neuroprotection by releasing growth factors like BDNF, VEGF, NGF, CNTF, and GDNF, which aid in neuronal survival and repair.

Fig. 4 Stem cell therapy and its effects on ischemic brain. (Marques, et al., 2019)

Transdifferentiation-Based Therapy for Stroke

Transdifferentiation is a process where a somatic cell directly transforms into another cell type without passing through a stem cell stage. This can occur naturally or through direct reprogramming of the cell's genome. In brain studies, astrocytes are commonly used in transdifferentiation research due to their high proliferation capacity and close lineage to neurons. Astrocytes in the subventricular zone can act as neural stem cells and can be reactivated in response to ischemic or traumatic brain injury. Transdifferentiation can be achieved through techniques like expressing transcription factors or microRNAs, often delivered via viral vectors or small molecules. One example is using adeno-associated virus (AAV9) to insert the NEUROD1 transcription factor, converting reactive astrocytes into functional neurons.

Fig. 5 Neuronal transdifferentiation of glial cells in functional neurons. (Marques, et al., 2019)

References

1. Marques, B. L., et al. (2019, November). The role of neurogenesis in neurorepair after ischemic stroke. In Seminars in cell & developmental biology (Vol. 95, pp. 98-110). Academic Press.
2. Mu, J. D., et al. (2023). The factors affecting neurogenesis after stroke and the role of acupuncture. Frontiers in Neurology, 14, 1082625.