The basal ganglia comprise a group of subcortical nuclei that form extensive connections with the cerebral cortex, thalamus, and brainstem, and are involved in a wide range of functions including motor regulation, cognitive processing, emotional modulation, and learning (Pott et al., 2009). This group of brain nuclei is of particular interest in neuronal replacement as it hosts the specific cell populations that degenerate in Huntington’s and Parkinson’s diseases. In Huntington’s disease (HD), GABAergic medium spiny projection neurons (MSNs) in the striatum are primarily affected while in Parkinson’s disease (PD) the dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) undergo degeneration.

Compared to the cortex and spinal cord, OL function and myelination in the basal ganglia is less studied. However, evidence suggests that this region’s distinctive axonal architecture and neuronal activity patterns have profound influence in OLs both locally and along the axons in the corpus callosum (Caldwell et al., 2023). Notably, axons of MSNs are myelinated (Bishop et al., 1982), while dopaminergic neurons localized in the SNpc are scarcely myelinated despite having long axons (Sulzer and Surmeier, 2013; Orimo et al., 2011; Braak and Del Tredici, 2004). The underlying mechanisms behind this distinction have not been explored, as studies explicitly comparing myelination of SNpc DA neurons with other neuronal types are largely absent. Nevertheless, to understand the contribution of OLs to PD, some reports have focused on studying the interactions of OPCs with DA neurons, even in regions where actual myelin sheaths are scarce. For instance, high-resolution imaging of the mouse midbrain revealed that NG2⁺ OPCs in the SNpc are abundant (in a 1:1 ratio with DA neurons) and their processes frequently envelop both the soma and axons of TH⁺ neurons (Fitzgerald et al., 2025). In addition, it has been shown that midbrain dopamine axons can synapse onto OLs in vivo and that some Olig2⁺/PDGFRα⁺ OPCs can express Drd1/Drd2 receptors (Caldwell et al., 2023), implying that dopaminergic fibers can directly signal to OPCs, potentially influencing myelination. Thus, OPCs make extensive axo-glial contacts in SNpc despite minimal myelin.

As SNpc DA neurons are scarcely or thinly myelinated, very few transplantation studies dealing with this neuronal population have assessed whether the grafts acquire myelination or affect the host OL population. Nevertheless, beyond myelination, DA neuron interactions with OLs and OPCs in the SNpc have been suggested to have a prominent role in the etiology of PD. Recent studies have identified a distinct cell type association between PD risk and OL-specific gene expression (Agarwal et al., 2020; Adams et al., 2024). For instance, some of studies have shown that PD-linked risk loci identified by genome-wide association studies (GWAS) associate strongly to OL transcriptional profiles (Bryois et al., 2020; Dehestani et al., 2024). Moreover, a recent single-nuclei multiomic study that profiled gene expression and chromatin accessibility of young, aged and PD human postmortem midbrain samples showed that OLs were both the major cell type in the midbrain and one of the most altered cell types in PD, and identified a “disease-associated” OLs subpopulation (Adams et al., 2024). When comparing differentially expressed genes (DEGs) among healthy and disease-associated OL populations, PD-specific changes included a reduction in multiple genes involved in myelination (i.e., MBP, MOBP, MOG), glial-neuron adhesion (i.e., CTNNA3, NRXN3), as well as an increase in stress-response genes (i.e., HSP90AA1, FKBP5) and well-known neurodegenerative markers, such as MAPT which contains multiple PD-associated single nucleotide polymorphisms (SNPs) (Adams et al., 2024). Furthermore, MRI studies in PD patients have revealed widespread changes in white matter, with most connections emerging from the basal ganglia showing a reduced myelin content (Boshkovski et al., 2022).

The heterogeneous myelin distribution of the basal ganglia and complex OL-DA neuron interactions add an extra layer of complexity to consider in neuronal replacement studies when discussing homotopic versus ectopic graft placement. A direct comparison between intranigral versus intrastriatal grafts using ventral mesencephalon (VM) fetal donor cells (Droguerre et al., 2022) or human ESC-derived midbrain DA neurons (Xiong et al., 2021) after 6-Hydroxydopamine (6-OHDA) injection into the SNpc in adult mice showed that, while both sent projections to appropriate dopaminergic targets, the intranigral grafts promoted better survival of DA neurons and the recovery of fine motor skills, whereas the intrastriatal grafts elicited higher inflammation/gliosis response at the site of the graft (Droguerre et al., 2022; Xiong et al., 2021). While both astrocyte and microglia reactivity were studied and showed an increase in GFAP⁺/C3⁺ and Iba1⁺/CD68⁺ populations in the intrastriatal compared to the intranigral grafts (Droguerre et al., 2022), oligodendrocyte and myelination responses to these transplants were not assessed. Whether or not homotopic or ectopic transplants acquire differential myelination or interact differently with the local OL population has not yet been explored. Encouraging observations have been reported from clinical trials in which fetal mesencephalic tissue was transplanted into the putamen and caudate nucleus of two PD patients. Follow-up assessments conducted after 11–16 years post-transplantation revealed sustained graft survival, with numerous dopaminergic neurons exhibiting long processes and forming dense neural networks within the grafts and the surrounding striatum. Notably, myelinated axons were observed in the grafted regions using Luxol fast blue staining (Li et al., 2008). However, the extent to which this myelination was attained, whether the axons corresponded to DA neurons or other type of tN, and whether it recapitulated the endogenous patterns was not studied.

In addition to the dopamine-based strategies to modify circuit activity in the basal ganglia, the transplantation of cells derived from the medial ganglionic eminence (MGE) has been assessed to alleviate motor symptoms in the 6-OHDA PD model (Martínez-Cerdeño et al., 2010). Following transplantation, MGE cells migrated away from the injection site and spread across the host striatum. By 4 weeks post-transplantation (wpt), ~75% of transplanted MGE cells expressed the mature neuronal marker NeuN and GABAergic markers. Moreover, these tNs exhibited several markers typical of striatal GABAergic interneurons, including as calbindin (CB), calretinin (CR), parvalbumin (PV), and somatostatin (SST). Although striatal interneurons are often myelinated, especially PV⁺ (Lousada et al., 2021), myelination was not specifically assessed in this study. Interestingly, one fourth of the transplanted MGE cells were NeuN negative and CNPase⁺, suggesting that a subpopulation of MGE cells differentiated into OLs (Martínez-Cerdeño et al., 2010). This represents an exciting avenue as MGE grafts could provide both neurons and OLs required to repair the damaged circuit. Whether the transplanted OLs have a preference to myelinate tN axons over host axons has not yet been explored.

Similar to PD, cell replacement therapy for HD has also advanced to clinical trials (Shah et al., 2025). While white matter dysfunctions have been widely reported in HD patients (Back et al., 2024), explicit reports of graft myelination in clinical and pre-clinical studies are scarce. Encouragingly, axonal tracing of fetal striatal transplants grafted into the excitotoxically lesioned striatum of rats revealed that these axons originate predominantly from DARPP-32-positive MSNs and extend exclusively in the caudal direction. The tNs axons form a single, well-defined bundle that follows the trajectory of the myelinated fibers of the internal capsule, ultimately branching into terminals within the globus pallidus. Electron microscopy (EM) analysis identified myelination in a couple of examples of these tNs striatopallidal axons (Wictorin et al., 1990); however, how many tNs have myelinated axons and the extent to which this myelination replicates the endogenous pattern remains uncharacterized. Notably, myelination within the graft site has not been consistently observed and appears to depend on factors such as the type of transplanted cells and the specific HD model studied. For instance, in the Q175 genetic mouse model of HD, human NSCs transplanted into the striatum differentiated into MSN- and interneuron-like cells but did not give rise to observable myelinated tracts under infrared illumination with differential interference contrast (IR-DIC) microscopy. The grafts were readily distinguishable from the surrounding host tissue, which appeared darker due to myelinated fiber tracts. In contrast, the grafts were more translucent and densely populated with diverse cell types (Holley et al., 2023), suggesting limited myelination within the graft. Further characterization is required to confirm this observation. In clinical trials, histological analysis of long-surviving HD graft patients has provided some evidence of possible myelination in graft tissue. In one case report, post-mortem examination 10 years post-transplant showed intense gliosis of bilateral caudate nuclei and putamen, as well as the unfortunate overgrown of masses and a cyst from the transplant. Staining of the graft site and circumscribed masses showed individual and bundled myelinated MBP⁺ axons which rarely appeared to cross the graft-host boundary (Keene et al., 2009). While this report provides evidence that transplant-derived axons can undergo myelination in the human brain, it remains unclear whether in this case this was promoted by the abnormal graft overgrowth observed in the patient. Therefore, these findings should be interpreted with caution.

Neuronal transplantation has been extensively studied as a strategy to repair SCI. A key goal is not only to form new relay circuits, but also to achieve proper myelination of the regenerated axons (Roman et al., 2024), since the spinal cord is heavily myelinated. The proportion of myelinated spinal cord axons that has been quantified varies across regions, species, age and techniques used (Saliani et al., 2017) and ranges from 40–60% in rat sacral spinal cord (Chung and Coggeshall, 1983), to an impressive >99% in lumbar mouse spinal cord (Schäffner et al., 2023). In the spinal cord, myelination is more advanced during early postnatal development compared to the brain (Hilscher et al., 2022). While brain and spinal cord OPCs have different spatial and temporal developmental origins, they both emerge from distinct waves in a ventral-to-dorsal temporal sequence (Vallstedt et al., 2005). Interestingly, spinal cord and brain OPCs converge in similar transcriptional profiles, despite their different developmental origins (Marques et al., 2018). On the other hand, mature OLs display notable transcriptional heterogeneity across different brain and spinal cord regions, giving rise to distinct subpopulations that have been characterized via single-cell (sc)-RNA sequencing (Marques et al., 2016; Hilscher et al., 2022; Weng et al., 2025). These transcriptomic subpopulations of mature OLs (MOL1-6) have different spatial distributions in the brain and spinal cord and their abundance fluctuates with age and pathology. For example, in the spinal cord, MOL5/6 population increases with age and shows a spatial preference for gray matter (GM), whereas the MOL2 population is predominantly found in white matter (WM) (Floriddia et al., 2020). This transcriptional heterogeneity is reflected at the functional level both in vivo and in vitro. For instance, MOLs enriched in the brain subventricular zone express a unique profile of transcription factors linked to development, while spinal cord-enriched MOLs are defined by a specific upregulation of immune-related gene signatures (Weng et al., 2025; Yaqubi et al., 2022). Interestingly, in vitro when cultured on synthetic microfibers designed to mimic a myelination substrate, spinal cord OLs formed longer myelin sheaths compared to their cortical counterparts, mirroring internodes in vivo (Bechler et al., 2015). Spinal cord OPCs also showed increased migration and differentiation capacities, which are regulated by region-specific factors such as SKAP2, a cytoplasmic adaptor protein involved in cytoskeletal remodeling (Ghelman et al., 2021).

Consequently, spinal cord transplants may be more readily myelinated than basal ganglia or cortical transplants. One of the few transplantation studies that quantitatively evaluated tN myelination showed that fetal rat spinal cord NPC grafts after C5 hemisection displayed myelination by host OLs in around 24% of tN axons emerging from the graft quantified 8–14 mm caudal to the lesion site (C8), with a G-ratio equal to that of axons in the intact spinal cord (Hunt et al., 2017). In addition to the myelination of tNs by host OLs, the contribution of transplanted cells to the pool of OLs and their role aiding remyelination and functional recovery has been shown to be relevant. Human, rat and mouse NSCs, ESCs and iPSCs have been shown to differentiate into both neurons and glia (including OLs and astrocytes) when transplanted into the injured spinal cord (Cummings et al., 2005; Erceg et al., 2010; Tsuji et al., 2010; Yasuda et al., 2011). Transplantation of myelin-deficient shiverer mutant NSCs in SCI showed that both wildtype and mutant NSC transplants prevented atrophic changes in the injured spinal cord and promoted axonal growth, but only wildtype transplants preserved/enhanced myelination and locomotor functional recovery (Yasuda et al., 2011). These data highlight the importance of graft-derived OLs to the transplant outcome. Human fetal-derived stem cells grown as neurospheres (hCNS-SCns) transplanted after SCI can migrate to areas of demyelination and differentiate into graft-derived OLs, which then remyelinate spared mouse axons (Cummings et al., 2005; Salazar et al., 2010). Intriguingly, evidence of human cytoplasmic antigen (SC121⁺) OLs myelinating mouse axons could be found by EM, but SC121⁺ axons from graft-derived neurons were not reported to be myelinated by neither graft nor host OLs (Cummings et al., 2005). In a follow up-study, colocalization of SC121 with the paranodal protein CASPR was observed within the white matter, suggestive of host mouse axons remyelinated by graft-derived OLs rather than myelination of tNs since SC121-positive axons rarely extended into the white matter (Salazar et al., 2010). Similarly, Tsuji et al. (2010) reported that iPSC-derived grafts can differentiate into neurons, astrocytes, and OLs. They observed graft-derived OLs myelinating host axons but did not provide evidence of graft-derived axons being myelinated. When human ESC (hESC)-derived motor neuron progenitors and hESC-derived OPCs are co-transplanted after SCI, myelination of transplanted cells was observed. The human-specific neuronal NF70⁺ fibers were surrounded with APC⁺ hNU⁺ OLs, indicating that transplant-derived OPCs can also myelinate tNS (Erceg et al., 2010). Further research is needed to characterize the individual contribution of graft-derived OLs and neurons to locomotor recovery as well as to understand whether tNs can be equally myelinated by transplant and host OLs in SCI. While tOLs can myelinate host axons, it remains unclear whether they are more efficient at this task than endogenous OPCs or surviving host OLs following transplantation. Importantly, the graft and its surrounding microenvironment differ from the original injury site, in part due to the “bystander effects” exerted by transplanted cells on the host parenchyma (Ben-Hur, 2008; Han et al., 2023; Weber et al., 2025). Donor cells are well known to secrete pro-survival, neurotrophic, and pro-myelinating factors that can enhance the proliferation, survival, and differentiation of host OPCs, thereby improving the overall capacity for endogenous myelination and remyelination (Einstein et al., 2009). However, the opposite has also been observed with the transplant exerting strong and sustained microglia activation on the surrounding host parenchyma (Zarb et al., 2025).

Another critical variable across SCI transplantation studies that can profoundly affect the outcome of the intervention is the extent and position of the injury. Most animal studies have focused on transplantation in sharp, unilateral, incomplete injury models (i.e., hemisection and hemicontusion) which present with limited neuron loss, immune response, and gliotic scarring of injury level (Wilcox et al., 2014). Nonetheless, most clinical trials have prioritized patients with complete SCI (Burns et al., 2003; Bretzner et al., 2011; Wilcox et al., 2014). Importantly, also the extent of myelin pathology differs following contusion or transection SCI (Siegenthaler et al., 2007). It has been observed that contusion injuries produce more widespread structural damage, significant white matter apoptosis, demyelination, limited remyelination, and a strong macrophage response that extends several millimeters beyond the lesion core. In contrast, transection injuries that are more common in transplantation studies, cause a more localized pathology, with apoptosis and demyelination largely restricted to the lesion epicenter (Siegenthaler et al., 2007). Given the variability in host microenvironment across SCI models, it is not surprising that the differentiation outcomes of the transplant also vary widely. Some studies suggest that the harsher the SCI, the more pro-astrocytic the graft niche becomes and less transplanted cells differentiate into neurons or OLs (Cao et al., 2001; Wang et al., 2008; Khazaei et al., 2020; O’Shea et al., 2022). Indeed, after injury Notch ligands (Khazaei et al., 2020) and myelin-associated factors such as Nogo (Wang et al., 2015) are upregulated in the spinal cord microenvironment and bias differentiation of transplanted cells toward more astrocytes. Nevertheless, there are reports after complete transection (Lu et al., 2012) or contusion (Cummings et al., 2005), where an important proportion of the grafts differentiated into mature neurons (20–30%). Thus, the distinct SCI microenvironments, the choice of donor cell sources, and the timing of transplantation are variables that all add to the wide differences observed in the proportions of graft cell populations.

The cortical gray matter exhibits unique myelination patterns that vary widely across different cortical regions, layers (Tomassy et al., 2016; Jokhi et al., 2024; Xu et al., 2024) and neuronal subtypes (Call and Bergles, 2021). This diversity is a hot topic of study in the field of myelination and is reviewed elsewhere (Foerster et al., 2019; Sherafat et al., 2021; Osanai et al., 2022; Weng et al., 2025). In brief, the mechanisms that control cortical myelination heterogeneity are poorly defined, and they are thought to involve a combination of factors. These include distinct signals from specific neuronal subtypes residing in each cortical layer (Jokhi et al., 2024), as well as intrinsic characteristics of OLs, such as their transcriptional and functional diversity (Marques et al., 2016; Floriddia et al., 2020; Pivoňková et al., 2024). Additionally, the developmental and maturation stage of OLs plays a role (Sun et al., 2018). Extrinsic cues from the local microenvironment, including astrocytes, microglia, and the extracellular matrix, also contribute to this complexity (Sherafat et al., 2021). OLs in the cortex are transcriptionally heterogeneous, with distinct subpopulations that preferentially myelinate specific types of axons (Weng et al., 2025; Foerster et al., 2019). It will be very important to understand to which extent this heterogeneity persists with aging, neurodegeneration and after injury. In addition to this intrinsic diversity, neuronal cues play a critical role in initiating and shaping myelination patterns. This is underscored by findings showing that mislocalization of deep-layer projection neurons to upper cortical layers leads to aberrant, ectopic myelination in those regions (Tomassy et al., 2014). Supporting this, recent work by Jokhi et al. (2024) demonstrates that ectopic expression of pro-myelinating signals that are normally associated with heavily myelinated deep-layer neurons, in upper-layer neurons is sufficient to induce myelination in otherwise sparsely myelinated upper layers.

This complexity and heterogeneity in the myelin network of the host circuits may pose a significant challenge to the successful integration of neuronal transplants that has so far been overlooked in the field. Notably, cortical transplants exhibit a high degree of regional integration specificity. Studies have demonstrated that only donor cells with the appropriate cortical regional identity can effectively contribute to the reconstruction of the damaged cortical circuits (Gaillard et al., 2007; Michelsen et al., 2015; Terrigno et al., 2018; Espuny-Camacho et al., 2018). For instance, mouse ESCs-derived tNs with visual cortex identity integrate successfully when transplanted into a lesioned adult visual cortex, however, the same neurons fail to integrate when grafted into the motor cortex, indicating that a match in region identity between grafted and host tissue is crucial for functional integration. EM analysis in this study revealed that some GFP-labeled tN-derived axons were ensheathed by host myelin in both the cortex and dLG following transplantation into the injured visual cortex. However, the extent of myelination was not quantified and only individual examples were shown, leaving the overall degree of myelination uncertain. Although these neurons also survived after transplantation into the motor cortex, their pattern of axonal projections was markedly different, with reduced innervation of the cortex, striatum, and thalamus (Michelsen et al., 2015). Importantly, the study did not report whether the non-specific projections in heterotopic transplants were similarly myelinated. Thus, the extent and specificity of tN myelination remain largely unknown, leaving open critical questions about how selective and region-appropriate myelination can be achieved in diverse transplant scenarios.

Despite extensive preclinical and clinical research in cortical transplantation across various injury models, direct evidence for the myelination of tN axons remains limited. While very few studies have reported the presence of myelinated tN-derived axons following transplantation in the cortex, these observations are often based on isolated examples rather than comprehensive or systematic analyses. This lack of quantification makes it difficult to draw firm conclusions about whether tNs can consistently acquire myelination at all, as well as the specificity, and functional relevance of tN myelination. Moreover, it remains unclear how the myelination of tNs compares to that of endogenous neurons in terms of pattern, thickness and general myelin dynamics. While some studies using models of cortical stroke, aspiration injury, and traumatic brain injury (TBI) have reported myelination of tNs from diverse donor sources, it remains unclear how many of the tNs are myelinated and if these neurons can acquire the complex, region-specific myelination patterns characteristic of the host cortex. One estimation of the extent of myelination that can be acquired by tNs comes from seminal work by Gaillard et al. (2007). In this study, a fragment of embryonic mouse motor cortex was transplanted immediately into an adult mouse brain after a part of the motor cortex was acutely aspirated. At 2 months post-transplant, both EM and IHC analyses revealed myelination of transplant-derived axons in the cortex, striatum, and internal capsule, with approximately 30% of GFP⁺ fibers also colocalizing with PLP. While this study offers valuable insight into the potential for tN myelination, the spatial pattern and variability of myelination across different grafts were not explored, making it difficult to assess the consistency and regional specificity of these findings. Moreover, since analyses were conducted at a single time point, it remains unclear whether the observed myelination is stable over time, or subject to dynamic changes.

Qualitative evidence for myelination of human tNs comes from cortically fated human iPSC-derived neuroepithelial-like stem cells (NES) transplanted into the rat somatosensory cortex following ischemic injury. Upon differentiation these tNs extended axonal projections across both hemispheres, and showed evidence of myelination at early, intermediate, and fully compacted stages, as confirmed by EM. Notably, many MBP⁺ fibers also stained for human-specific markers for mitochondria and STEM121, indicating that graft-derived OLs were functional and actively producing myelin (Palma-Tortosa et al., 2020). However, it remains unclear whether these tOLs preferentially myelinate transplant-derived or host axons, and how many of the tNs were myelinated. These limitations highlight the need for longitudinal, region-specific, and quantitative studies to fully understand the extent, stability, and functional relevance of tN myelination following cortical transplantation.

Numerous studies have shown that the CNS inflammatory response that is upregulated upon injury and neurodegeneration can have detrimental effects on OL differentiation and myelination. OL are highly susceptible to damage under pathological conditions due to several factors (Dent et al., 2015). Notably, OLs operate at one of the highest metabolic rates among brain cell types to support the synthesis and maintenance of extensive myelin sheaths (Meschkat et al., 2022). This leads to the accumulation of harmful byproducts such as reactive oxygen species (ROS) and renders OLs particularly prone to oxidative injury. Further aggravating their susceptibility, OLs exhibit limited antioxidant defenses with low production of glutathione, thereby impairing their ability to counteract oxidative stress (Connor and Menzies, 1996; Thorburne and Juurlink, 1996). Consequently, conditions associated with metabolic or oxidative strain can overwhelm these cells, triggering apoptotic (Dewar et al., 2003) and likely ferroptotic pathways. Additionally, pro-inflammatory cytokines can initiate cell death; interferon gamma (IFNγ) compromises proliferation of OPCs, while tumor necrosis factor alpha (TNFα) induces apoptosis in differentiated OL (Horiuchi et al., 2006; Jurewicz et al., 2005). These cells are also at risk of excitotoxic death resulting from unregulated glutamate and ATP release, which heightens membrane permeability to extracellular calcium and promotes apoptosis (Mcdonald et al., 1998). Such pathophysiological features are hallmarks of conditions that are targets for neuronal transplantation interventions, namely TBI, SCI, stroke, and localized basal ganglia neurodegeneration (HD and PD). Targeting these pathways to improve OL viability might improve transplant integration in these models, however, this might not be a “one size fits all” solution as each of these pathologies present with very different environmental cues, even though commonalities can be found, such as complement activation (Thomas et al., 2022). Moreover, differential inflammatory responses across different brain regions may play a role in regulating localized OL activity. For instance, we have shown that there are profound differences in grey matter glial reactivity, including NG2 glia proliferation, when the white matter is also injured or not (Mattugini et al., 2018).

To better understand the key checkpoints that tNs must overcome to successfully integrate into different brain environments, it is important to consider how integration varies depending on the surrounding pathology. When endogenous neurons are ablated through apoptosis, resulting in minimal reactive gliosis and inflammation, tNs can achieve near-perfect integration with appropriate brain-wide synaptic inputs and functional properties comparable to endogenous neurons (Falkner et al., 2016). However, this level of integration is no longer observed when tNs are transplanted into environments affected by TBI, aging, or amyloid pathology. Using the same brain-wide input connectome analysis, studies have shown that integration is significantly impaired or exuberant under these conditions (Grade et al., 2022; Thomas et al., 2022). These findings highlight the powerful influence of the injury environment on the establishment of synaptic inputs to tNs. For the purposes of this review, we broadly categorize these pathological environments into two groups: acute injuries (TBI, SCI, and stroke) and chronic neurodegenerative conditions (PD and HD). It is important to note, however, that acute injuries often evolve into chronic states, blurring the boundaries between these categories. Finally, it is also important to note that very little to nothing is known about how the transplant affects the progress of the lesion environment.

While this review has primarily focused on the influence of the host environment on graft survival and integration, substantial evidence also highlights the critical role of the intrinsic properties of transplanted cells. For successful integration, donor cells-whether developmentally immature fetal progenitors or more advanced in vitro patterned and matured cells-must adapt to the complex and highly organized architecture of the host neural network. Numerous studies have directly compared various sources of donor cells, such as iPSCs, ESCs and fetal-derived neural progenitors, within the same host models. Such comparative analyses provide valuable insights into how donor cell origin and intrinsic characteristics impact graft viability, differentiation potential, and therapeutic efficacy across different neurological conditions.