Oligodendrocytes (OLs) produce myelin and provide metabolic support to axons via the myelin sheath. This sheath is a lipid-based protective coating composed of altered cell membranes. It envelops myelinated axons, allowing for the rapid and efficient transmission of electrical signals along these pathways. Myelination is required for the fully developed central nervous system (CNS) to function optimally. The disruption of CNS myelin, whether induced by injury, pathological degeneration, or genetic conditions, results in significant functional deficits and frequently shortens lifespan. The targeted loss of myelin in the central nervous system, as seen in demyelinating disorders such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), leukodystrophies, and so on, causes a rapid deterioration in neurological function.

The need for continuous myelination along the entire axon necessitates a perfect match between the number of OLs produced and the number of axons to be myelinated. OLs arise from oligodendrocyte precursor cells (OPCs), and their ability to differentiate persists until adulthood. However, in adults, OPCs differentiate at a substantially slower rate than throughout the developmental phases [1], [2]. The procedure of producing the necessary number of OLs involves several successive steps. To create OPCs, neuroepithelium cells must first be activated. These precursors begin a long distance from the axons they will eventually myelinate, and in order to do so, they must actively migrate throughout the CNS and come to a halt at the precise location. OPCs proliferate rapidly, particularly in growing white matter, aided by specific growth factors. After a sufficient number of progenitor cells have been produced, OL precursors differentiate and mature into immature OLs. In addition to being OL progenitors, they also interact with blood vessels, regulate neuroinflammation, and transmit neuronal synaptic signals [3]. Nonetheless, the fundamental function of adult OPCs is to differentiate into myelinating OLs, which is required for both myelin repair and learning [4], [5]. OPCs and OLs have numerous ion channels and neurotransmitter receptors [6], [7], allowing them to respond to neuron activity. This neuronal activity has been shown to regulate OPC proliferation, differentiation, OL myelination, and may play a role in learning-induced myelination [8], [9]. During these periods, various growth factors are required to promote the proliferation and survival of OL progenitors.

Immature OL precursors respond to bFGF, which is found in the embryonic CNS. The expression of different FGF receptors determines the varied responses of OL lineage cells to growth factor stimulation along their embryonic trajectory [11]. Platelet-derived growth factor (PDGF) is an important survival factor for OLs. PDGF-A is broadly distributed throughout the intact CNS, produced by both astrocytes and neurons [12], [13]. PDGF-A overexpression results in a considerable increase in the population of spinal cord OL precursors, whereas PDGF-A deficiency results in a significant reduction in these precursor cells. bFGF stimulates the expression of PDGF receptors on these precursors, and when coupled with PDGF, bFGF increases the long-term proliferation of OL precursors. Oligodendrocyte development is also influenced by a number of additional growth and trophic factors. For example, neurotrophin-3 (NT3) has been demonstrated to induce mitosis in pure optic nerve OLs [14]. Retinoic acid and its derivatives appear to inhibit the progression of immature OLs within the lineage, while concurrently encouraging differentiation at later stages [15]. In this review, we tried to explore how oligodendrogenesis is impacted by the glial-lineage-specific growth factors during the lifespan of a living organism. We also discussed how these growth factors are altered during homeostatic and neuro-pathological conditions.

Oligodendrocyte precursors proliferate significantly after committing to the ventricular zone. The early stages of this proliferation occur inside the ventricular and subventricular zones (SVZ), but the majority of OL proliferation happens after migration into the developing white matter [10]. Throughout these stages, growth hormones including as FGF, PDGF, BDNF, EGF, and IGF-1 are critical in encouraging the proliferation and survival of OL precursors. In general, the differentiation of OL precursors is characterized by the termination of cell cycle activity and the development of the primary myelin glycolipid, galactocerebroside (GC). Oligodendrocytes have a multi-branched phenotype, and their development is marked by a coordinated rise in the production of numerous essential myelin components, such as myelin basic protein (MBP) and proteolipid protein (PLP) [11]. Some major growth factors that have been known to participate in OL development are as follows:

EGF plays crucial roles during development of the nervous system. Because its expression is only detectable later in brain development, it is widely accepted that EGF is not mitogenic at the start of neural development [12], [13]. EGF binding to the EGF receptor (EGFR) stimulates enzymatic activity. In the adult mammalian CNS, SVZ cells produce OLs. These cells have the characteristics that identify neural stem cells (NSCs), including as growth, multipotency, and self-renewal [12]. EGFR regulates how SVZ precursors grow in response to brain injury [14], [15]. When the EGFR is inhibited, brain sub-SVZ precursor growth is lost. EGF/EGFR activates the phosphoinositide 3-kinase (PI3K) and extracellular-signal-regulated kinase 1/2 (ERK1/2) pathways, resulting in the proliferation of NSCs [16], [17]. EGF promotes intracellular cAMP accumulation and subsequent PKA activation, which activates cAMP response element binding protein (CREB) by activating adenylate cyclase and blocking cAMP-specific phosphodiesterase [18], [19]. The migration of adult and embryonic neural precursors is strongly controlled by EGFR signaling [20]. This is associated with increased focal adhesion kinase (Fak) and Akt phosphorylation [21], [22]. EGFR activation has also been associated with enhanced gliogenesis (Fig. 1) [23]. EGF has a considerable influence on the fate, amplification, and migration of SVZ cells expressing EGFRs near the lateral ventricles [24], [25]. Because OPCs originate in the spinal cord (SC), which contains glial progenitors that generate both astrocytes and OLs, their localization is not restricted to certain locations of the ventricular zone and the SVZ during various stages of brain development [26]. SVZ astrocytes have been shown to produce OPCs when EGF is present [27]. Neuron-derived substances such as neuregulins (NRGs) are significant regulators of CNS myelination because they influence the differentiation and proliferation of OPCs and/or OLs, especially during CNS development [28]. Surprisingly, NRGs' EGF-like domain is both necessary and sufficient for their ErbB receptors to be activated [28]. EGF should be considered a potent promoter due to its favorable effects on OLs and astrocytes, as well as certain extracellular matrix (ECM) components [29]. Despite being heterogeneous cell populations [30], autocrine stimulation can be established since OLs [31] and OPCs [32] both produce EGF and possess EGFR. In the OL lineage, differentiation and proliferation are negatively associated because OPCs do not differentiate during division; instead, they differentiate into OLs and myelinate once mitogens are removed. Remyelinating OLs are generated by an endogenous pool of OPCs distributed throughout the adult central nervous system [33]. Because 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) is well recognized as an OL marker at all stages of myelination, EGF stimulation of (CNPase, EC 3.1.4.37) is extremely important [34]. The role of EGF in OL formation is summarized in Table 1. In summary, EGF can modulate NSC population during early stages of neural development and adulthood via PI3K and ERK1/2 pathways but its direct effect on NSC differentiation is still debatable. EGF can, however, affect oligodendroglial lineage progression in OPCs and OLs via NRGs.

Neurogenesis is influenced by the FGF family's FGFR-1, FGFR-2, and FGFR-3 proteins. While inactivating each resulted in asymmetrical divisions and neurogenesis, co-activating FGFR-1 and 3 promoted symmetrical divisions of NSC. During development, OPCs migrate to different areas of the brain and differentiate into myelin-producing cells [35]. FGF is one of many growth factors that influence OL development [36]. NSCs separated from the dorsal spinal cord that do not produce the OL lineage can be induced by FGF2 to express NG2 and Olig2, resulting in the development of OLs as illustrated in Fig. 1 [37]. Brain morphogenesis includes important processes such as the migration of immature neurons, glial cells, and NSC, the creation of neural networks, and the recovery from injury. The influence of FGF/FGFR signaling on OL development, on the other hand, is controlled by FGFR expression variability. Mature OLs express FGFR2, while early and late OPCs express FGFR3. They both express FGFR1 but not FGFR4 [38]. During OL development and maturity, each FGFR performs specific functions. While FGFR3 signaling controls the transition of late OPCs into OLs, FGFR2 influences OL differentiation and myelination, and FGFR1 may transduce signals that increase early OPC proliferation and migration [36]. Because they initiate myelination, govern myelin thickness independent of OL differentiation, and aid in the remyelination of persistently demyelinated lesions, FGFR1 and FGFR2 are required for CNS myelination [39]. Furthermore, by regulating distinct stages of the OL lineage, the downstream mediators of these FGFR signaling pathways, ERK1/2 and PI3K/AKT/mTOR (mammalian target of rapamycin), gradually influence myelination. This is of particular importance considering the subsequent immature OL stages and the transition from early to late OPCs are mediated by ERK1/2 signaling while immature to mature OLs require the mTOR signaling pathway [39].The FGF family has many members, each of whom plays a distinct role in myelination. FGF2 promotes OPC migration and proliferation while inhibiting terminal differentiation. Furthermore, FGF2 has an effect on mature, post-mitotic OLs, lowering FGFR1-mediated re-entry into the cell cycle and myelin proteins while enhancing process elongation through FGFR2 activation [40]. To suppress OPC differentiation, FGF8 and its related subfamily member FGF17 activate FGFR3. However, in differentiated OLs, FGF9 enhances myelination by specifically activating FGFR2 [41]. FGF18 acts similarly in differentiated OLs and OPCs by activating FGFR3 and FGFR2, respectively [40]. In vitro and in vivo studies show that circulating FGF21 promotes OPC proliferation, but this impact is dependent on the presence of β-Klotho [42]. The amount of FGF21 in healthy people's cerebrospinal fluid (CSF) is approximately 60 % less than that in the peripheral circulation, hence FGF21 transit into the CNS is restricted under normal conditions [43]. When the blood-brain barrier fails, FGF21 enters the CNS and directly stimulates myelination. Furthermore, FGF21 regulates Vascular Endothelial Growth Factor 2 (VEGF2) receptor expression, which affects OPC migration and, indirectly, OL formation and remyelination [44], [45]. The role of several FGFs in OL formation is summarized in Table 1.It can be surmised from the above discussion that FGF has a far more widespread coverage in terms of determining the lineage progression of NSCs than EGF. The transition of OL precursors from early to late stages and their migration, the maturation of OLs and finally the myelination of CNS neurons as well as the remyelination of demyelinated axons are encompassed by different isoforms of FGF.

Tyrosine-based hormones called THs influence nearly all body cell types to control CNS development, including oligodendrogenesis [46]. The growth and differentiation of OLs depend on these two hormones: the functionally active triiodothyronine (T3) and its precursor, thyroxine [47]. The two types of thyroid hormone receptors (TRs), TR-α and TR-β are one of the ways that THs operate to promote oligodendrogenesis. These TRs are nuclear receptors that change the expression of genes by binding to thyroid response elements in DNA either as homodimers or heterodimers [48]. Furthermore, TRs dimerize with retinoid X receptors and other nuclear receptors expressed in OLs [49] to influence oligodendrogenesis [50].

Apart from its effects on proliferation, T3 also stimulates the differentiation of embryonic NSCs in vitro, encouraging cells to take on a mixed glial lineage [51]. In particular, the amount of OPC triples when T3 is present. The glycoprotein transferrin, which raises TRα1 expression, is necessary for this impact [52]. Additionally, OPC development is favored when adult-derived NSCs are treated with T3 [53], [54]. In addition, TH plays a crucial role in regulating OPC differentiation and proliferation. Specifically, T3 stimulates OPCs to differentiate into mature OLs and leave the cell cycle [55]. It appears that TRs have a role in the mechanics of this transition, which are still partially understood [56]. In vitro, OPC proliferation is completely stopped when T3 binds to TRα1 [57], and OPC proliferation continues when TRα1 is absent [58]. As OPCs multiply, TRα2 mRNA, which codes for a dominant-negative version of TRα, similarly declines, potentially establishing a favorable environment for TRα1 activity and subsequent OPC differentiation [59]. Therefore, OPCs are prompted to quit the cell cycle by many types of TRα. The effects of TR on OPC differentiation are a little more intricate. Since only differentiated OLs express TRβ, it is hypothesized that TRβ helps terminal differentiation into mature OLs, whereas TRα receptors facilitate the effect of TH on OPC differentiation [60]. Though it is unknown whether these effects are indeed TRβ dependent or whether this external elevation of TRβ occurs at the same TREs as TRα, TRβ overexpression and TRβ agonist applications both promote OPC differentiation [56].

THs change the morphology of OLs and cause OL maturation [53]. Through interactions with MBP promoter areas and transcriptional regulation of other genes, including myelin OL glycoprotein and glutamine-synthase, THs specifically support the morphological and functional maturation of OLs [61]. These results are supported by the observation that TH deficiency shortens the elongation process of mature OLs [62] and delays the development of MBP and the myelin-associated enzyme CNPase [61]. Also, T3 can enhance the amount of pre-myelinating OLs, the complexity of OL morphology, and the expression of MBP by working with 9-cis retinoic acid, which binds to RXR [63], [64]. Additionally, THs improve OL survival throughout that period. The capacity of TH to control survival-specific growth factors such as neurotrophin-3 and IGF-1 may be the cause of this impact [65]. OLs no longer need TH to survive after this window of time [66].

TH is a key ligand that propels this activity because of the significance of integrins in controlling oligodendroglial growth [67]. TH regulates the time and development of OLs since the blood level of TH peaks during the active myelination phase of the fetal and postnatal phases [68].T4 therapy has been demonstrated to drastically reduce OL mortality and hypomyelination under hypoxic-ischemic (HI) damage conditions [69]. It stimulates oligodendrogenesis and regulates OL metabolism by inducing angiogenesis in hypoxia-related white matter disorders [70]. By encouraging OPC proliferation in the early stages of development and subsequently altering the shape of post-mitotic OLs—a maturation process that enhances myelination—data have also identified T4 as a modulator of white matter injury (WMI) from the premature brain [69].T3 (the active form of TH) has also been shown to have an effect in vitro and in vivo due to the activity of T4. When OPCs were found in rats with acute and chronic T3 shortages, a thorough investigation revealed that they produced more pre-OLs but less mature OLs [62]. The upregulation of myelin gene expression, including PLP, during T3 administration supports the latter finding, which points to the significance of T3 during the later stages of OL development i.e., maturation and myelination [62]. Together, these findings suggest that T4 and T3 function as mitogens, promoting development, differentiation, and maturation while controlling the OL cell cycle, which leads to the production of the intricate myelin sheath around neuronal axons [71]. However, in peripheral nervous system (PNS) and CNS tissues, TH transporters, deiodinases (DIOs), and TH receptors regulate their bioavailability [72]. T3 was the most successful growth factor in inducing OL maturation and differentiation of OPC and neural stem/progenitor cells (NSPC) in vitro when compared to the other growth factors, brain-derived neurotrophic factor (BDNF), NT3, and sonic hedgehog (Shh), all of which are known to enhance OL differentiation [79], [80], [81]. The role of T3 and T4 in OL development is tabulated in Table 1.

PDGF is found in whole-blood serum and is subsequently isolated from human platelets. It promotes cellular division of fibroblasts, smooth muscle cells (SMCs), and nerve glial (NG2) or OPCs, thereby classified as a mitogen [73]. It is composed of four distinct polypeptide chains, PDGF (A-D), which combine to form four homo-dimers, PDGF-AA, PDGF-BB, PDGF-CC, and PDGF-DD, as well as one hetero-dimer, PDGF-AB. Isoforms of PDGF are produced by fibroblasts, SMCs, NG2, and platelets to facilitate cell survival, growth, proliferation, differentiation, and other cellular functions. PDGF isoforms are also expressed in the CNS to aid neuronal development. PDGF-BB regulates the blood-brain barrier (BBB), and its disruption can contribute to the pathogenesis of neurological disorders (ND) like Alzheimer's disease (AD), Parkinson's disease (PD), and MS [74].

The development of OLs in their early stages is dependent on PDGF, as tabulated in Table 1. During neuronal development, it mediates the process of OPCs differentiating into mature OLs by binding to its receptor PDGFR-α and preventing premature differentiation [75]. As development advances, levels of PDGF decrease, causing OPCs to cease proliferating and start differentiating into myelinating OLs. The expression of OPCs is mediated by various signaling pathways within the CNS and is influenced by PDGF-AA. A recent study found that certain signaling molecules influence OL differentiation and CNS myelination from below the cell, as illustrated in Fig. 1. According to the study, Gab1 (Grb1-associated binder protein, a central hub that interacts with other stimuli for cellular responses) acts downstream of the target receptor to interact with signaling proteins like PI3K, ShP2 (Tyrosine Phosphatase-2), and PDGFR-α to regulate the mitotic process of OLs in the CNS [76]. Regulation within the CNS becomes increasingly important due to its complex nature. Transcription factors and certain cell surface proteins in the extracellular matrix, including integrins, interact with the PDGFR-α to control the proliferation of OPCs into OLs. Proteins like neuropilin-1 (Nrp1), activated on the demyelinated corpus callosum, stimulate the phosphorylation of PDGFR-α, which in turn facilitates the signaling of PDGF-AA [77]. The trans-activation of PDGFR-α provides signals of the activation of PDGF-AA in the presence of Nrp1 on the neighboring microglia. This boosts the proliferation of OPCs on the corpus callosum but not on the cortex, showing its specificity in the regulatory mechanism of remyelination [78].

The overexpression of PDGF is crucial in OPC differentiation, but it can result in an accumulation of cells that fail to mature into differentiated OPCs in the CNS environment for remyelination. MS is caused by an immunological attack that disrupts the myelin due to demyelination. PDGF stimulates the proliferation of OPCs, but in MS, a chronic inflammatory environment prevents OPCs from proliferating into myelinating OLs. In traumatic brain injury (TBI), the upregulation of PDGF following injury leads to an initial increase in OPC proliferation. However, certain cytokines in the microenvironment limit the remyelination process, resulting in prolonged injury [79]. In neurological disorders such as ALS and AD, PDGF's effectiveness could be compromised by the deregulation of signaling pathways, leading to demyelination. Recent studies have found that the controlled activation of PDGF aids the remyelination process. The primary isoforms for OPC proliferation are PDGF-AA and PDGF-BB, which bind to the PDGFR-α ligand on the surface of OPCs. Once this binding occurs, PDGFR-α undergoes autophosphorylation, recruiting other signaling molecules PI3K/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) essential for OPC proliferation [80]. When PDGFR-α binds to RTK, it undergoes autophosphorylation, with the resulting phosphorylated site serving as docking points for additional signaling proteins. Upon phosphorylation, a tyrosine residue recruits one regulatory p85 subunit and one catalytic p110 subunit of PI3K to activate PI3K. Upon activation, PI3K facilitates the conversion of phosphatidylinositol-4–5-bisphosphate (PIP2) to phosphatidylinositol-3–4–5-triphosphate (PIP3). PIP3 functions as a second messenger that recruits AKT, which is subsequently activated by phosphoinositide-kinase 1 (PDK1) and mechanistic target of rapamycin complex 2 (mTORC2). The downstream effect of AKT mediates cell survival, growth, and proliferation, which are essential for the maturation of OL lineage cells [81].

On the other hand, in the MAPK/ERK pathway, autophosphorylation of tyrosine residue results in the binding of growth factor-receptor-bound protein-2 (Grb2) on tyrosine residue. Now, Grb2 recruits son of sevenless (SOS), which acts as a guanine exchange factor for Ras, a small GTPase protein. SOS facilitates the exchange of guanosine diphosphate (GDP) to guanosine triphosphate (GTP) on Ras. Once Ras is activated, it triggers the phosphorylation of MAP kinase by interacting with Raf kinase. Raf activation phosphorylates MEK, a dual-specificity protein that activates ERK on both threonine and tyrosine residues. MEK then phosphorylates ERK, fully activating it. The downstream effect of ERK is involved in the early development of OPCs into mature, myelinating OLs [82]. PDGFRα-mediated AKT signaling is more relevant in the early stages of OPC proliferation, while PDGFRα-mediated ERK signaling is important for the differentiation process [83]. Thus, the integration of findings across various models ranging from developmental studies to disease conditions like MS, TBI, ALS, and AD clearly highlights that while PDGF is essential for remyelination, its therapeutic application must be carefully calibrated. Overactivation may lead to proliferative blocks, while underactivation can result in insufficient OPC recruitment.

The protein BDNF is coded by the human BDNF gene. It is a member of the neurotrophin family, related to the canonical nerve growth factor, specifically NGF. The BDNF gene plays a vital role in producing the protein BDNF, found in the brain and spinal cord [84]. BDNF promotes the growth, survival, proliferation, differentiation, and maintenance of neuronal cells and OPCs in the CNS [85] as shown in Fig. 1. BDNF acts as a neurotrophin, offering neuroprotection and contributing to the myelination of OL lineage cells in the central nervous system. The protein has a strong affinity for binding to the tropomyosin receptor kinase B (TrkB) receptor, which is crucial for the proliferation of OPCs. BDNF/TrkB signaling is closely related to OPC proliferation, maturation, and differentiation. The TrkB receptor, present on the cell membrane of OLs binds to BDNF and activated to promote myelination and increases the density of OPCs in the CNS, both in vitro and in vivo [84], [85], [86], [87]. BDNF also promotes neurogenesis by interacting with its receptor TrkB via the PI3k/Akt and MAPK/ERK pathways, much like PDGF [88].

BDNF establishes a conducive environment for OL function [86], [88]. In addition to its function in neurogenesis, BDNF displays robust pro-myelination properties in demyelination scenarios, indicating its potential for treatment in neurological disorders such as MS. Studies focusing on activating TrkB in OL lineage cells have shown improved myelin repair in the corpus callosum. The comparison of myelin repair involved two treatments: TDP6, a BDNF mimic, and LM22A-4, a small molecule TrkB agonist. The two compounds exhibited distinct signaling pathways—TDP6 accelerated the maturation of OLs, while LM22A-4 augmented the population of OL precursor cells in the central nervous system [89]. Huang et al. [90] conducted a study to examine how histone acetylation, particularly through sodium butyrate, mitigates white matter damage in neonatal rats. The results indicated a correlation between diminished acetylated histone levels and WMI disease. Inducing histone acetylation with SB facilitated OL differentiation and conferred protection against damage. The protective effect correlated with enhanced BDNF synthesis and the activation of the BDNF-TrkB signaling pathway. The role of BDNF in OL development is also documented in Table 1.

Integrating all these studies reveals a coherent picture: BDNF is indispensable for healthy myelination and offers therapeutic potential in a variety of demyelinating and developmental white matter disorders. With its proven ability to enhance OPC proliferation, promote OL maturation, and repair myelin in vivo, BDNF, especially through TrkB, emerges as a powerful candidate for therapies aimed at CNS remyelination and neuroprotection.

Insulin-like growth factor, particularly IGF-1 [91], plays a crucial role in facilitating growth, survival, and differentiation across various cell types. Research interest has been significant due to its potential applications in treating demyelinating illnesses and CNS traumas as shown in Table 1, particularly in its role in OL differentiation and myelination. IGF has roles in the CNS's development, homeostasis, and repair processes in vivo [92]. It continues to play a significant role during early brain development, even if its expression is lower in adulthood. By interacting with IGF receptors, particularly IGF-1R, this growth factor triggers downstream signaling cascades that regulate critical biological functions. IGF-1 is essential for the growth and maturation of OPCs during CNS development [93]. Knockout mice lacking IGF-1, for example, display significant impairments in brain development, myelin levels, and OL numbers, underscoring the role of IGF-1 in promoting myelination during critical developmental periods [94]. IGF-1 also enables OPCs to migrate towards areas of active myelination, thereby maintaining an even spread of OLs throughout the brain and spinal cord [93], [94].

The effects of IGF-1 on OLs are mediated through the stimulation of specific intracellular pathways, particularly the PI3K/Akt and MAPK signaling cascades. The PI3K/Akt pathway promotes the growth and differentiation of OPCs by enhancing cell survival and preventing apoptosis. The MAPK pathway simultaneously affects cellular differentiation and proliferation, ultimately enhancing myelin production. IGF-1's capacity to regulate these pathways is especially advantageous in demyelinating conditions such as MS. IGF-1 has demonstrated substantial potential in promoting regeneration and repair in adult models of CNS damage or disease. IGF-1 triggers remyelination in MS or spinal cord injury, through the induction of local OPC proliferation and maturation into mature OLs, as illustrated in Fig. 1 [95], [96]. IGF-1 diminishes oxidative stress and neuroinflammation, both prevalent impediments to effective regeneration. IGF-1 has been found to be crucial for cytoskeletal remodeling, a process required for OL morphological development. Other molecules like thyroid hormones, neurotrophins, and extracellular matrix components often augment the effects of IGF-1.

Preclinical studies indicate that delivering IGF-1 directly to the site of a problem via spinal injections or specially designed scaffolds made of biomaterials could lead to improved remyelination and functional recovery. IGF-1-based treatments may also help disorders related to brain development, such as leukodystrophies, which are marked by abnormal myelination. Administration of IGF-1 early after birth in animal models of hypoxic-ischemic (HI) brain damage has been found to reverse myelination problems, making it a strong candidate for use in humans as a treatment [97]. Severe demyelination often occurs after traumatic brain injuries and spinal cord injuries, making long-term difficulties with functioning worse. IGF-1 may be key in reducing the impact of these injuries by encouraging the development of OL cells and the growth of new myelin. Combining IGF-1 with activity-dependent myelination strategies like physical therapy and rehabilitation may also improve outcomes further [96].

In summary, the overall body of research strongly supports IGF-1 as a key mediator of OPC development, OL maturation, and myelin repair across both developmental and pathological conditions. The activation of PI3K/Akt and MAPK/ERK signaling by IGF-1 enables a wide variety of functions, including survival, migration, morphological maturation, and cytoskeletal restructuring. These effects, when properly modulated, provide substantial therapeutic benefits in both pediatric and adult central nervous system disorders. The similarities with other growth-promoting and brain-cell-supporting pathways, like those driven by PDGF and BDNF, highlight the significance of IGF-1 within a more extensive network of signaling pathways that regulate CNS function and adaptability. The combined evidence suggests a future where IGF-1-based treatments are tailored for combination therapies that repair myelin and enhance neurological results in cases of demyelinating conditions and trauma.