Neuronal migration into injured tissue: mechanisms and therapeutic strategies for brain regeneration

Abstract

Neuronal migration is a crucial process not only for brain development but also for neural regeneration after injury. It has been reported that some new neurons generated in the ventricular-subventricular zone (V-SVZ) migrate toward tissue injured by ischemic stroke and other forms of brain damage. These migrating neurons can partially compensate for lost neurons and contribute to functional recovery, including improvements in motor function. Therefore, understanding the mechanisms that regulate neuronal migration is expected to facilitate the development of novel therapeutic strategies that enhance endogenous neural regeneration after brain injury.

In this review, we discuss the migratory mechanisms of new neurons generated in the V-SVZ and summarize current insights into strategies aimed at promoting neuronal migration and neuronal replacement in the injured brain.

Highlights

• •New neurons generated in the V-SVZ migrate in the intact and injured brain by regulating cytoskeletal dynamics.
• •New neurons migrate to the injured region and replace lost neurons, contributing to the recovery of motor and sensory functions.
• •Biomaterials and pharmacological approaches that promote neuronal migration toward injured regions are being actively investigated and may lead to fundamental therapies for brain injury.

1. Introduction

For many years, neurogenesis was considered to be restricted to the embryonic period, and it was widely believed that lost neurons could not be regenerated. However, neural stem/progenitor cells have been reported to persist in the postnatal brain, including in the ventricular-subventricular zone (V-SVZ) and the dentate gyrus of the hippocampus [[1], [2], [3]]. Since these early reports, the extent and biological significance of neurogenesis in the adult human brain have remained subjects of active debate. Recent studies have provided differing interpretations regarding the persistence of neurogenesis in the adult human dentate gyrus, but commonly indicate that hippocampal neurogenesis is more prominent during early life and declines markedly during postnatal development and aging [4,5]. A similar developmental decline has also been described in the human V-SVZ, where neural stem/progenitor cells and neuronal migration are more evident in early life but appear to become progressively restricted with aging [6,7]. In addition, immature neurons have been reported in regions of the postnatal amygdala, and some of these cells appear to retain migratory capacity [8,9]. Thus, rather than focusing solely on whether neurogenic cells persist in the adult human brain, an important question is the extent to which they support robust ongoing neurogenesis, long-distance migration, and functional neuronal integration in adulthood. In contrast, in rodent models, the generation and migration of new neurons from the V-SVZ are well established. These immature neurons migrate in chain-like structures along the rostral migratory stream (RMS), reach the olfactory bulb, differentiate into inhibitory interneurons and integrate into the neural circuitry [[10], [11], [12]]Fig. 1, Fig. 2, Fig. 3.

Fig. 1.

Modes of neuronal migration in the intact brain

(a) Structure of migrating new neurons generated from the V-SVZ and the stepwise process of saltatory migration. (b) Structure of the growth cone and leading process. At the growth cone, L1-CAM, Shootin1b, and cortactin interact with F-actin to generate forces that drive forward movement. Extension of the leading process is regulated by F-actin and microtubules. In addition, branching and orientation of the leading process are controlled by the kinase activity of PAK3. Celsr3 and Kif2a regulate the branching and the length of the leading process by modulating microtubule dynamics. (c) The frequency of swelling formation accompanying centrosome translocation is regulated by Gmip. During migration, the primary cilium transiently protrudes into the extracellular space, where Gpr161 regulates microtubule dynamics. (d) Somal and nuclear translocation is promoted by contractile forces generated by actomyosin activation at the rear of the soma.

Fig. 2.

Cell-cell interactions during neuronal migration in the intact and injured brain

During migration along the RMS and toward injured regions, new neurons utilize various surrounding cell types as migratory scaffolds, including other new neurons, astrocytes, blood vessels, and radial glial cells.

Fig. 3.

Regenerative medicine strategies based on the control of neuronal migration

Biomaterial-based approaches and pharmacological interventions promote neuronal migration from the V-SVZ toward injured brain regions, potentially contributing to functional recovery, including improvements in motor function.

Following brain injury such as ischemic stroke, some new neurons derived from the V-SVZ migrate toward the lesion site and contribute to the replacement of lost neurons [13,14]. More recently, it has been demonstrated that promoting the migration of new neurons toward the injured region enhances neural regeneration and leads to functional recovery, including improvements in locomotor performance [[15], [16], [17], [18]]. Importantly, these migratory mechanisms have been shown to be conserved not only in mice but also in the common marmoset and humans [7,[19], [20], [21]]. These findings underscore that elucidating the regulatory mechanisms of neuronal migration represents a critical challenge for both understanding brain function and developing regenerative therapies.

In this review, we provide an overview of the molecular and cellular mechanisms underlying neuronal migration in both the intact and injured brain and discuss strategies for translating these insights into regenerative medicine.

2. Neuronal migration in the intact and injured brain

New neurons derived from the V-SVZ exhibit a polarized morphology characterized by the extension of a single leading process from the soma, and a growth cone composed of actin-based filopodia and lamellipodia forms at the tip of the leading process [10,[22], [23], [24], [25], [26]]. Neuronal migration occurs while neurons remain in an immature state and proceeds through three sequential steps: (1) extension of the leading process, (2) centrosome translocation, and (3) nuclear translocation (nucleokinesis) [27] (Fig. 1). This migratory mode is called saltatory migration and is also a characteristic feature of neuronal migration during embryonic development [28,29].

New neurons migrating toward injured regions also exhibit chain migration similar to that observed in neurons migrating along the RMS, but their migratory speed is markedly slower [16]. In addition, these neurons exhibit gene expression profiles that are distinct from those of the intact brain [30]. In the following sections, we provide an overview of the mechanisms underlying neuronal migration in both the intact and injured brain.

2.1. Cytoskeletal dynamics during neuronal migration

2.1.1. Control of migration by extension of the leading process and the growth cone

The leading process and its growth cone sense surrounding extracellular matrix (ECM) components and molecular cues and regulate the direction of migration through dynamic reorganization of the cytoskeleton [31,32]. Various receptors such as deleted in colorectal cancer (DCC) and bone morphogenetic protein (BMP) receptors are expressed on the growth cone. Ligands (guidance factors) such as Netrin-1 and BMPs bind to these receptors and activate downstream signaling, thereby regulating actin and microtubule dynamics and leading to the elongation and retraction of the growth cone [33].

In the initial stages of neuronal migration, Shootin1b, an axonal clutch molecule, accumulates at the growth cone. Its interaction with cortactin and L1-cell adhesion molecule (L1-CAM) generates a backward traction force, which promotes elongation of the leading process. Furthermore, mechanical stimulation of the plasma membrane associated with this extension has been reported to trigger the opening of Tmem63b, thereby inducing somatic translocation [25,34].

In addition, the planar cell polarity (PCP)–associated molecule Celsr3 forms a complex with Kif2a and regulates the migratory cycle and leading process branching by modulating microtubule stability [35]. During embryonic neuronal migration, the activity of p21-activated kinase 3 (PAK3) determines both the number and orientation of leading process branches, thereby regulating tangential and horizontal modes of neuronal migration [36]. Thus, the structure of the leading process and the growth cone is tightly regulated through control of microtubule and actin dynamics, enabling precise spatiotemporal regulation of neuronal migration.

In injured regions, chondroitin sulfate proteoglycans (CSPGs), which are repulsive glycoproteins, are highly expressed and induce growth cone retraction and collapse. As a result, the functions of the leading process and the growth cone are impaired, thereby inhibiting neuronal migration [26]. Furthermore, new neurons migrating toward the injured region exhibit not only reduced length of the leading process but also impaired directional persistence. In addition, excessive cell–cell adhesion has been observed in these neurons compared with migrating neurons in the intact brain, resulting in reduced migratory efficiency [18]. The molecular basis of these abnormalities remains largely unclear, but disruption of intracellular signaling and cytoskeletal regulation caused by inhibitory environmental factors such as CSPGs is likely to be involved.

2.1.2. Regulatory mechanisms of migration mediated by the centrosome and the primary cilium

During leading process extension and nuclear translocation, new neurons form a transient dilated structure within the leading process termed the swelling, which contains the centrosome and the Golgi apparatus. Near the swelling, RhoA is activated, and the Rho-GTPase-activating protein Gmip negatively regulates RhoA activity to control the frequency of swelling formation and migration cycle [37].

The centrosome is an intracellular organelle involved in microtubule organization and contributes to the establishment and maintenance of neuronal polarity. In addition, primary cilia are present in both medial ganglionic eminence (MGE)–derived neurons [38] and V-SVZ–derived new neurons [39], and these structures are essential for controlling the direction of neuronal migration. In migrating neurons, the centrosome is positioned anterior to the nucleus during the resting phase. After extension of the leading process, the centrosome advances and projects the primary cilium into the extracellular space, which is subsequently reabsorbed into the cell during nuclear migration.

During migration, cAMP hotspots form in the centrosomal region, where they regulate the frequency and directionality of centrosome translocation via PKA signaling while maintaining the structural integrity of the primary cilium [40,41]. Furthermore, the primary cilium, which is exposed to the extracellular environment, is enriched with the mechanosensitive receptor Gpr161. Activation of this receptor in response to mechanical stimuli regulates neuronal migration through cAMP-dependent control of microtubule dynamics [42]. In addition, the primary cilium modulates Sonic hedgehog (Shh) signaling and contributes to the determination of migratory direction in embryonic cortical neurons by regulating microtubule polymerization and Golgi apparatus organization [38,43]. Thus, swelling formation and the centrosome-derived primary cilium are considered to constitute a central regulatory mechanism that integrates the control of the direction and dynamics of neuronal migration through modulation of microtubule organization.

Following brain injury, Shh signaling is activated in astrocytes and neural stem cells, contributing to neurogenesis and the maintenance of neural stem cell populations [44]. Moreover, the primary cilium serves as a signaling hub that harbors a wide array of receptors and integrates extracellular cues to regulate cytoskeletal dynamics in an environment-dependent manner. This suggests that in new neurons migrating toward injured tissue, the primary cilium may also modulate migratory direction and the frequency of centrosome translocation in response to local microenvironmental signals [45,46].

2.1.3. Somal translocation and nuclear migration

Nuclear translocation is driven by actomyosin contractile forces that depend on RhoA signaling and intracellular calcium signaling [47,48]. In cerebellar and cortical migrating neurons, the nuclear membrane protein complex of Sun2 and Syne2 (Nesprin-2) interacts with the dynactin complex and induces nuclear migration driven by microtubule-derived traction forces [49]. In addition, Nesprin-2 interacts with kinesin to enable dynamic remodeling of nuclear morphology, thereby facilitating efficient migration accompanied by nuclear rotation [50]. Furthermore, new neurons express the mechanosensitive Ca²⁺ channels Piezo1 and Tmem63b, which induce calcium influx in response to mechanical stimuli such as cell–cell adhesion and fluid shear stress and regulate neuronal migration by modulating myosin activity [34,51].

The peripheral hormone ghrelin regulates cytoskeletal dynamics via PI3K signaling and is transported to the brain through the bloodstream. In migrating new neurons, an actin cup forms at the rear of the soma, and ghrelin has been reported to increase both the duration of somatic translocation and the migratory distance by prolonging the persistence of the actin cup [52].

During brain injury such as ischemic stroke, extracellular matrix molecules including collagen and fibronectin accumulate in the peri-infarct region, leading to the formation of a glial scar. Although direct experimental evidence for alterations in somatic and nuclear translocation under injury conditions has not yet been reported, it is conceivable that the increased tissue density associated with scar formation physically restricts the extension of the leading process and nuclear movement, thereby potentially impairing neuronal migration. A comprehensive list of factors regulating these migratory mechanisms is summarized in Table 1.

Table 1.

Factors involved in neuronal migration.

Protein	Definition	Expression	Function	Reference
Dcx	Microtubule binding protein	GC/LP/Cell body	Regulation of neuronal morphology and migration	Koizumi et al. [53]
Drebrin	Actin binding protein	GC/LP/Cell body	Regulation of neuronal morphology and migration	Sonego et al. [54]
Fascin	Actin bundling protein	GC/LP/Cell body	Regulation of neuronal morphology and orientation	Sonego et al. [55]
Cortactin	Actin binding protein	GC	Regulate growth cone area and neuronal migration speed	Nakajima et al. [26]
Shootin1b	Axonal clutch molecule	GC/LP/Cell body	Binding cortactin and L1-CAM to drive leading process extension and somal translocation	Minegishi et al. [25]
Kif21b	Kinesin family	GC/LP	Regulate cytoskeletal dynamics and neuronal migration	Alvarez J.R et al. [56]
Cdk5	P-directed serine/threonine kinase	LP/Cell body	Regulation of the speed and direction of neuronal migration	Hirota et al. [57]
Gmip	RhoGAP	LP/Cell body	Negative regulation of swelling formation and neuronal migration	Ota et al. [37]
Tmem63b	Mechanosensitive cation channel	LP/Cell body	Mediate tension-triggered Ca2+ signaling and drive somal translocation	Minegishi et al. [34]
Gpr161	Mechanosensitive orphan G protein coupled receptor	PC	Regulate somal and centrosomal translocation by regulating cAMP concentration	Paillard et al. [42]
CXCL12/Cxcr4	Chemokine/receptor	PC/Plasma membrane	Regulate cAMP/cGMP balance to set the tangential migration mode of cortical migration	Atkins et al. [41]
Kif3a	Kinesin family	PC/Cytoplasm	Regulate ciliogenesis and saltatory movement	Matsumoto et al. [39]
PSA-NCAM	Cell adhesion molecule	Plasma membrane	Regulation of neuronal morphology and neuronal chain	Chazal et al. [58]
N-cadherin	Cell adhesion molecule	Plasma membrane	Regulation of neuronal adhesion and migration	Jinnou et al. [15]
β1 integrin	Heterodimeric cell surface molecules	Plasma membrane	Regulate the formation of neuronal chain	Belvindrah et al. [59]
CSPG/HSPG	Chondroitin/heparan sulfate proteoglycan	Plasma membrane	CS: inhibit axon elongation. HS: promote GC extension and axon elongation	Nakajima et al. [26]
Celsr3	GPCR	Plasma membrane	Regulate the direction and velocity of neuronal migration	Hakanen et al. [35]
Sema3E/PlexinD1	Neural secreted protein/receptor	Plasma membrane	Regulate neuronal morphology and terminate neuronal migration in OB	Sawada et al. [60]
Dchs1/Fat4	Atypical cadherin	Plasma membrane	Regulate PCP and lateral migration	Zakaria et al. [61]
Piezo1	Mechanosensitive cation channel	Plasma membrane	Trigger actomyosin force transmission for neuronal migration in confined tissue	Nakazawa et al. [51]
Ghrelin/Ghsr1	Peptide hormone/receptor	Plasma membrane	Increase neuronal migration speed by promoting somal translocation	Ogino et al. [52]
Wnt/Fzd/Diversin	Glycoprotein/receptor/component of Wnt-PCP signaling	Plasma membrane /Cytoplasm	Regulate PCP and proliferation of neuronal migration	Ikeda et al. [62]
Dishevelled2/Vangl2	PCP signal core molecule	Plasma membrane /Cytoplasm	Regulate PCP signals in neuroblasts and morphogenesis of new neurons in the OB	Hirota et al. [63]
Slit1/Robo2	Guidance molecule/receptor	Cytoplasm/Astrocyte	Regulation of neuronal migration	Kaneko et al. [16]
Rac1/Vav3	Small GTPase/GEF	Cytoplasm/Nucleus	Regulation of shape and cytoskeleton of migrating neuroblasts	Khodosevich et al. [64]
Fyn	Src Family Tyrosine Kinase	Cytoplasm	Regulate neuronal migration and neuroblast detachment from the RMS	Fujikake et al. [65]
PAK3	Serine/Threonine kinase	Cytoplasm	Regulate LP dynamics and orientation of cortical migration	Viou et al. [36]
Nogo-a/NgR1	Neuroendocrine/receptor	Cytoplasm/Astrocyte	Support neuroblast migration through the activation of Rho/ROCK pathway	Rolando et al. [66]
Fmrp/Map1b	Ribonucleoprotein/microtubule associated protein	Cytoplasm /Microtubule	Regulate microtubule dynamics and neuronal migration	Messaoudi et al. [67]
Dlgap4	Guanylate kinase	Cytoplasm	Regulate neuronal morphology and neuronal migration	Romero et al. [68]
Sun2/Syne2	Nuclear membrane protein	Nuclear membrane	Regulate nucleokinesis of radial migration and interact with dynein/dynactin complex to drive force from microtubule	Zhang et al. [69]

The molecular mechanisms underlying neuronal migration in the intact brain are being systematically elucidated. In contrast, although phenomena such as disrupted migratory directionality and reduced migratory efficiency have been observed in the injured brain, the molecular mechanisms governing these alterations remain largely unclear. This represents an important knowledge gap that warrants further investigation in future studies.

2.2. Neuronal migration and cellular scaffold

New neurons migrate by appropriately utilizing surrounding scaffold structures present in their microenvironment, in addition to the morphological changes and saltatory migration described in the previous section (Fig. 2). New neurons migrating along the RMS form a chain-like structure, and because they establish adherens junction–like structures during this process, it has been suggested that new neurons use each other as mutual scaffolds to support their migration [53]. In addition, astrocytes and blood vessels are present within the RMS, and these structures actively interact with migrating neurons. Specifically, interactions between Slit1 released from new neurons and Robo2 expressed in astrocytes [16], interactions between β1 integrin on new neurons and Laminin in the vascular basement membrane [54], and further regulation of neuronal migration by blood flow velocity and Ghrelin signaling [52] have been reported. During embryonic brain development, radial glial cells extend from the subventricular zone to the cerebral cortex and serve as scaffolds that guide neuronal migration.

These mechanisms of neuronal migration that utilize blood vessels, astrocytes and radial glial cells as scaffolds have been reported to operate not only in the intact brain but also during migration toward injured tissue (e.g., blood vessels [14], astrocytes [16], and radial glia [15]). Therefore, applying these scaffold-dependent migratory mechanisms may provide a strategy to promote tissue regeneration in the injured brain.

3. Applications for regenerative medicine

In injured brain tissue caused by conditions such as ischemic stroke, the loss of neurons leads to motor dysfunction. One proposed strategy to ameliorate this deficit is to recruit endogenous new neurons to the injured region, thereby replacing lost neurons. In recent years, a variety of approaches aimed at promoting neuronal migration toward injured tissue have been reported (Fig. 3). In this section, we provide an overview of recent advances in these strategies.

3.1. Transplantation of scaffold biomaterials

Biomaterials are materials that possess biocompatibility and biodegradability and support tissue repair after transplantation. In recent years, materials containing ECM components, such as collagen, have been developed and are increasingly applied in the field of regenerative medicine.

To efficiently guide new neurons to injured regions and achieve functional recovery, it is important to design biomaterials with the following objectives: (1) providing a scaffold for neuronal migration, (2) supplying chemoattractive signals that guide neurons toward the injured site, and (3) promoting neuronal survival and differentiation after migration.

3.1.1. Providing a scaffold for neuronal migration

In injured tissue, neuronal migration efficiency is reduced due to multiple factors, including the accumulation of necrotic cells, increased angiogenesis, and excessive adhesion among new neurons. Therefore, introducing ECM-containing biomaterials that mimic the migratory environment of the intact brain may represent an effective strategy.

Laminin is a basement membrane glycoprotein that regulates cell adhesion, migration, and proliferation. New neurons express its receptor, β1 integrin, and the interaction between laminin and β1 integrin regulates migratory speed as well as the migration–pause cycle. It has been reported that transplantation of laminin-containing gelatin sponges into the injured cortex promotes neuronal migration toward the lesion site [54,55].

Furthermore, transplantation of sponges containing the adhesion molecule N-cadherin has been shown to promote neuronal migration toward the injured region and also lead to improvements in motor function [15]. In addition, transplantation of a hydrogel in which N-cadherin is incorporated into a self-assembling peptide–modified RADA scaffold has been shown to promote recovery of sensorimotor function [17].

3.1.2. Guidance of neuronal migration

The growth cone of new neurons senses the surrounding microenvironment and determines the direction of migration. This process is regulated by both structural changes in the growth cone itself and responses to guidance cues mediated by specific receptors.

In injured tissue, the repulsive molecules CSPGs are highly upregulated and inhibit growth cone extension through their receptor protein tyrosine phosphatase sigma (PTPσ). In contrast, heparan sulfate proteoglycans (HSPGs) attenuate the inhibitory effects of CSPGs and promote growth cone extension. Transplantation of HSPG-containing gelatin nonwoven scaffolds has been shown to suppress growth cone disruption, promote neuronal migration, and improve motor function [26]. Furthermore, biomaterials containing chemoattractive factors, such as the neurotrophic factors hepatocyte growth factor (HGF) [56] and glial cell line-derived neurotrophic factor (GDNF) [57,58], as well as the chemokine C-X-C motif chemokine ligand 12 (CXCL12)/stromal cell-derived factor-1 (SDF-1) [59], have also been developed. These materials have been reported to promote neuronal migration toward the injured region and contribute to the recovery of brain function.

3.1.3. Maintenance and maturation of neurons

Functional recovery requires not only promoting neuronal migration but also suppressing cell death at the injury site and inducing appropriate neuronal differentiation and maturation. Akt signaling plays an important role in cell survival, and dysregulation of this pathway can influence neuronal survival after injury. It has been reported that administration of the Akt activator SC-79 suppresses cell death and improves the survival rate of new neurons without affecting their proliferation [60]. Furthermore, hydrogels containing brain-derived neurotrophic factor (BDNF) have been reported not only to promote neuronal migration toward the injured cortex but also to induce neuronal differentiation and maturation after migration [61].

3.2. Pharmacological intervention

In addition to surgically providing scaffolds, strategies that modulate intrinsic migratory mechanisms through pharmacological intervention have also been proposed.

In injured tissue, neuraminidase is secreted from activated glial cells and cleaves polysialic acid (PSA) on the surface of migrating neurons, leading to excessive cell–cell adhesion and impaired migration. Inhibition of neuraminidase activity by administration of the neuraminidase inhibitor zanamivir suppresses PSA cleavage, thereby restoring proper neuronal migration and improving motor function [18]. Furthermore, in neurons with migration defects caused by mutations in Dchs1 and Fat4, which are genes associated with heterotopia (ectopic gray matter), administration of the AMP-activated protein kinase activator metformin has been reported to improve migration through the regulation of autophagy [62]. Thus, combining biomaterial-based scaffold design with drug repositioning strategies may broaden the potential for promoting neural regeneration and functional recovery after brain injury.

4. Cross-species comparison

Most of the findings discussed in this review are based on rodent models, and careful consideration of anatomical and molecular species differences is essential when extrapolating these results to humans.

From an anatomical perspective, postnatal new neurons in mice primarily migrate toward the olfactory bulb through the RMS, whereas in humans, widespread migration toward the frontal lobe has been reported during the first several months after birth [7]. Primates possess fundamentally larger brain volumes than rodents, resulting in greater physical distances between the V-SVZ and lesion sites in the injured brain. Consequently, chemoattractive signals released from injured regions may become attenuated before reaching the V-SVZ. In addition, the highly developed white matter tracts in primates may function as physical barriers to cell migration, thereby further limiting regenerative responses [63].

Moreover, at the molecular level, recent single-cell analyses have demonstrated that, although fundamental molecular programs underlying neurogenesis are largely conserved across species, human immature neurons exhibit species-specific gene expression profiles [64]. For example, genes encoding subunits of vacuolar-type ATPase (v-ATPase, including ATP6V1A, ATP6V0C, and ATP6V1B2), are highly expressed in human immature neurons. However, their precise roles in neuronal migration and neural regeneration in the injured brain remain unclear. This represents an important knowledge gap that warrants further investigation.

Therefore, to successfully translate findings from basic research into clinical applications, it is critically important to bridge these interspecies differences through studies using non-human primate models such as common marmosets [21], as well as larger-animal models including microminipigs [65], which serve as intermediate platforms between rodents and humans.

5. Limitations and future perspectives of therapeutic strategies

Despite considerable progress, several challenges still hinder the clinical application of these regenerative therapeutic strategies. Although biomaterial transplantation provides a powerful structural scaffold, concerns remain regarding immune responses and surgical invasiveness [66]. To overcome these limitations, it will be important to develop three-dimensional scaffolds with high cellular permeability and physicochemical properties compatible with brain tissue, such as self-assembling peptides and fibrous nonwoven materials.

Pharmacological approaches are generally limited by the permeability of the blood–brain barrier (BBB). However, in the injured brain, the BBB is locally disrupted, allowing even poorly permeable agents to reach lesion sites. Therefore, the major challenge is not merely BBB penetration but rather avoiding rapid systemic clearance and minimizing off-target adverse effects in vivo.

Future therapeutic strategies will likely benefit from integrated approaches that combine both modalities. Furthermore, it is important to recognize that neuronal migration represents only one component of the complex process of brain regeneration. In the future, combining migration-promoting strategies with approaches that activate endogenous neural stem/progenitor cells, promote their proliferation, and guide the appropriate differentiation of immature neurons may pave the way toward meaningful functional brain regeneration. In parallel, to overcome the limitations imposed by species differences, it will be essential to advance translational studies using not only rodent models but also non-human primate models and human tissues.

6. Conclusion

In this review, we have summarized the molecular and cellular mechanisms underlying neuronal migration, the processes responsible for the recruitment of newly generated neurons to injured brain tissue, and potential strategies for regulating these mechanisms and processes in regenerative medicine.

In the intact brain, new neurons generated in the V-SVZ undergo stepwise saltatory migration to reach the olfactory bulb. Although numerous molecules involved in this process have been identified, the overall network of molecular interactions and the integrated regulatory mechanisms governing neuronal migration remain incompletely understood. However, neurons migrating toward injured tissue appear to utilize mechanisms that are largely shared with those operating in the intact brain. Therefore, a deeper and more integrated understanding of neuronal migration in the intact brain is expected to facilitate the development of strategies that efficiently recruit and guide neurons toward injured regions.

Currently, treatment for brain injuries such as stroke relies primarily on symptomatic therapies centered on rehabilitation, and definitive strategies for neural regeneration have not yet been established. In addition to recent advances in biomaterial-based approaches that promote endogenous neurogenesis, combining these strategies with cell-based therapies—such as the generation and transplantation of iPS cell-derived neural progenitor cells—may provide a promising approach for functional reconstruction of injured brain tissue. Furthermore, integrating surgical interventions with pharmacological strategies that intrinsically enhance neuronal migration may contribute not only to the recovery of motor function but also to improvements in cognitive function.

Future studies integrating the molecular mechanisms of neuronal migration with biomaterial engineering and pharmacological modulation will be crucial for establishing clinically applicable regenerative therapies for brain injury.

Author contributions

All authors wrote and edited the manuscript.

Declaration of generative AI and AI-assisted technologies in the manuscript preparation process

During the preparation of this work the authors used ChatGPT, Gemini, and DeepL in order to check grammar, spelling and references. After using these tools, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.