Direct neuronal reprogramming: emerging therapeutic strategies for neurodegenerative disorders.

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Learn more: PMC Disclaimer | PMC Copyright Notice Ann Med . 2026 Apr 15;58(1):2654230. doi: 10.1080/07853890.2026.2654230 Search in PMC Search in PubMed View in NLM Catalog Add to search Direct neuronal reprogramming: emerging therapeutic strategies for neurodegenerative disorders Arooja Tyagi Arooja Tyagi a Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, India Visualization, Writing – original draft, Writing – review & editing Find articles by Arooja Tyagi a , Vijendra Prabhu Vijendra Prabhu a Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, India Writing – review & editing Find articles by Vijendra Prabhu a , Prasoon Agarwal Prasoon Agarwal b National Bioinformatics Infrastructure Sweden (NBIS), SciLifeLab, Division of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden Writing – review & editing Find articles by Prasoon Agarwal b , Praveen Kumar Praveen Kumar a Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, India Conceptualization, Writing – review & editing Find articles by Praveen Kumar a, ✉ Author information Article notes Copyright and License information a Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, India b National Bioinformatics Infrastructure Sweden (NBIS), SciLifeLab, Division of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden ✉ CONTACT Praveen Kumar [email protected] Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, India. Roles Arooja Tyagi : Visualization, Writing – original draft, Writing – review & editing Vijendra Prabhu : Writing – review & editing Prasoon Agarwal : Writing – review & editing Praveen Kumar : Conceptualization, Writing – review & editing Received 2025 Oct 24; Accepted 2026 Mar 29; Collection date 2026. © 2026 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( http://creativecommons.org/licenses/by-nc/4.0/ ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent. PMC Copyright notice PMCID: PMC13084837  PMID: 41986248 Abstract Background Treatment of brain injuries and neurodegenerative disorders is a critical challenge due to poor regenerative capabilities of the central nervous system. The current therapeutic strategies are primarily focussed on treating the symptoms than addressing the core issue of loss of neurons. Despite advances in stem cell therapies and surgical alternatives, they are not always successful due to challenges like immune rejection and limited efficacy. Direct neuronal reprogramming of endogenous somatic cells is a promising approach to restore lost neurons. This review evaluates traditional reprogramming techniques and their limitations, explores novel in-vivo strategies that address older problems, and analyse clinical trial outcomes to identify key knowledge gaps to guide future research. Discussion Traditional neuronal reprogramming is based on in-vitro ectopic expression of lineage-specific transcription factors. To overcome hurdles posed by in-vitro reprogramming, such as insertional mutagenesis, and variable efficiency, in-vivo approaches have emerged. These techniques employ small molecules, nonviral gene delivery, and CRISPR-based activation to reduce protocol complexity and improve cell survival. Combined methodologies integrate transcription factor cocktails with epigenetic modifiers, microRNAs, and neurotrophic factors, and show further enhancements. Despite these advances, translation to clinical applications has been modest. Early-phase trials report limited functional improvements and highlight risks of off-target effects, inconsistent delivery specificity, and unresolved immunogenicity Conclusions Direct neuronal reprogramming offers a viable strategy for replenishing neuronal cell mass in neurodegenerative diseases and brain injuries through autologous therapy. Novel in-vivo and combined approaches show promise in addressing the shortcomings of traditional methods. However, further preclinical validation, comprehensive safety assessments, and uniform frameworks are essential for clinical translation. Future studies should prioritize refining delivery platforms, minimizing off-target reprogramming events, and developing robust biomarkers to monitor conversion efficiency and functional outcomes. Keywords: Cell plasticity, transdifferentiation, small molecules, CRISPR, personalised medicine, autologous therapy SUSTAINABLE DEVELOPMENT GOALS: SDG 3: (Good Health and Well-being) KEY MESSAGES This article aims to explain direct neuronal reprogramming as focused treatment for the root causes of neurodegenerative diseases, replenishing lost neuronal cell mass. In-vivo reprogramming of resident astrocytes and neighbouring CNS cells to specific subclasses of neurons is possible using various methods which include ectopic expression of transcription factors, CRISPR, miRNAs, small molecules etc. Neuronal reprogramming also has surgical applicability, in the case of traumatic injury to the brain, nerve replacement surgeries and ischemic strokes. Techniques with high efficacy have been demonstrated in multiple pre-clinical and clinical trials around the world. 1. Introduction Neurons are a pivotal part of the central nervous system (CNS) [ 1 ]. They are the only cells, which have the capability to send and receive signals, without which the brain fails to communicate with the rest of the body, rendering someone functionless [ 2 ]. They are electrically excitable [ 3 ] and are made up of three functional parts- dendrites, soma and axons [ 4 , 5 ]. Dendrites are the cell ends and can receive and transmit signals, axons are responsible for carrying signals throughout the neuron while soma is the main body, holding the nucleus [ 3 ]. Dendrites also produce local proteins for axonal transport of the signals [ 2 ]. At the axonal terminal, chemical signalling molecules – neurotransmitters, neuromodulators and neurohormones – are released to convert electrical signals to chemical signatures to help in crossing the synapse [ 6 ]. Phenotypic differentiation is a complicated process [ 7 ], especially when it comes to neurons due to their complicated structures. CNS cells are generated by the expression of various factors as well as exposure to various hormones. Ciliary neurotrophic factor (CNTF) and thyroid hormone (T3) are common lineage restriction factors and are the mainly responsible for cell fate commitment to CNS cells [ 8 ]. Basic fibroblast growth factor (bFGF) has been noted to define neural tube identity [ 9 ]. Neuronal commitment and caudal tube development is influenced by the presence of Sonic Hedgehog proteins and transforming growth factor (TGF-β) [ 9 ]. Bone morphogenetic proteins BMP2 and BMP4 have been studied and identified to stimulate neurogenesis [ 8 ]. Through in-vitro glial differentiation, it has been observed that CNS stem cells efficiently transition to astrocytes via a single pioneer factor [ 8 ]. However, a similar factor for neurons has not been identified, owing to its complex and fine structure [ 8 ]. Oligodendrocyte-type 2-Astrocyte (O-2A) cells when exposed to bFGF, CNTF, T3, neutrophils and platelet-derived growth hormone resulted in the increase of oligodendrocytes, which produce myelin sheath for axons [ 8 ]. Neuronal reprogramming represents an innovative approach to convert non-neuronal cells into functional neurons without passing through a pluripotent state [ 10 ]. While studies have suggested that cell fate commitment of neurons occurs by a different mechanism or by different factors, it may also be possible that it is influenced by the presence of multiple cells [ 10 ]. Since such restrictions are not completely known for neurons, multiple processes have been explored to achieve neuronal reprogramming [ 5 ] These include the use of different sets of transcription factors (TFs), miRNAs, CRISPR and 3D scaffolds to improve cell turnover and yield [ 11 ]. These have been discussed in detail further on in this review. Despite substantial progress, key knowledge gaps exist, which prevent its translation to a clinical alternative. Low and variable reprogramming efficiency, especially across varying cell types along with incomplete functional maturation remain critical roadblocks [ 12 , 13 ]. Additionally, the identification of reliable single TF or cocktail of TFs to completely rewire the epigenetic memory of the somatic cell remains to be of high interest [ 14 , 15 ]. Additionally, a major gap in the field remains to be poor temporal synchronization and cell heterogeneity during differentiation [ 16 ]. These reasons prevent the induced neurons from gaining complete electrophysiological properties and synaptic integration with the native tissue [ 14 , 16 ]. Irrespective of the challenges, due to the potential applicability in treating neurodegenerative diseases and brain injuries ( Figure 1 ), these processes have garnered significant interest [ 17 ]. Applicability of neuronal reprogramming is diverse. It is a beneficial alternative to surgical complications as well, since medical and surgical alternatives to treat ischemia and traumatic brain injuries have high mortality rates and multiple parameters invalidate surgery as an alternative for many candidates [ 5 , 18 ]. General considerations such as age, level of distal injuries, laceration patterns, chronic injuries, risk of neuroma development at suture sites, etc., greatly influence the outcome of brain surgeries [ 19 ]. Figure 1. Open in a new tab Some potential applications of direct in-vivo neuronal reprogramming in the brain. Mouse has been used to depict organisms commonly used for research and preliminary trials. GABA: Gamma–Aminobutyric Acid; Glu: Glutamate; iN: induced Neurons; iDAN: induced Dopaminergic Neurons (Created with BioRender.com). Ageing is also a complex cellular and molecular process wherein there is a decline in the functional capacity of a cell causing challenges in tissue maintenance ultimately leading to mortality [ 20 , 21 ]. Neurodegenerative diseases such as Parkinson’s (PD) and Alzheimer’s (AD) are hard to treat since there are no comprehensive treatment plans for the condition, only for the symptoms [ 20 ]. Underlying causes of these diseases are the death of dopaminergic neurons in the case of PD [ 22 , 23 ] and death due to build-up of proteins around memory-neurons in the case of AD [ 20 ], which are irreversible processes. In a societal context, the Alzheimer’s Disease International projected the current number of affected people to triple by 2050, reaching approximately 150 million people, with about 70% of the affected persons belonging to low income and middle-income countries [ 20 ]. The projections for PD are uncertain due to the scarcity of country-specific data, however a systemic analysis from Global Burden of Disease estimated that the prevalence of PD has increased by 74% from 1990 and 2016 and will maintain this trend [ 24 , 25 ]. This context urges the community to provide alternatives. While there are multiple approaches being studied to treat neurodegenerative diseases, the possibility of replacing damaged cells with “new” ones is of particular interest [ 21 , 26 , 27 ]. Current therapeutics are still of limited capacity across three axes, pharmacological, surgical and cell based [ 28 ]. They do not meet the clinical need for healthy, new cells to replace the old, diseased ones [ 29 ]. Pharmacological treatments are limited to providing symptomatic relief and fail at halting or reversing neuronal loss [ 29 , 30 ]. Additional constraints such as that of the blood brain barrier, off target effects and long-term side-effects reduce the scope of further development [ 30 ]. Surgical interventions on the other hand, include deep brain stimulation, which are highly invasive, patient specific and as mentioned before, limited to only a specific demographic [ 30 ]. Cell-based therapies show the most promise, however current challenges faced include poor graft survival, inadequate functional integration and immune rejection, which require further exploration to convert cell based and reprogramming based therapies to become a safer and more efficient alternative [ 29 ]. This review, hence, enunciates neuronal reprogramming as a relevant topic in neuroscience and regenerative medicine, and discusses the overview of the strategies, current updates and limitations. The literature discussed in this review was collected through PubMed and Scopus, primarily focussing on studies published in the last 20 years, spanning from both concepts and experimental validation to clinical trials. Studies which elucidate on the underlying molecular mechanisms, directly addressing the conversion of somatic cells to neurons and demonstrating the clinical relevance of neuronal reprogramming were selected for this review. Emphasis was also placed on studies with quality and reproducibility in terms of clearly described methodologies, appropriate controls and their citations. 2. Traditional approach to neuronal reprogramming There are multiple approaches to neuronal reprogramming exploiting different aspects of the cell fate determination. Traditional methods focus on in-vitro reprogramming using transcription factors and viral delivery methods [ 15 ]. Traditional reprogramming operates through gene regulatory network remodelling using pioneer factors such as Ascl1 or through a cocktail of factors such as the BAM factors, as explained further. These factors bind to closed chromatin regions and recruit chromatin remodelers to enhance the activation of neurogenic enhancers [ 31 , 32 ]. Concurrently, some TFs are used for repression of lineage specific genes of the source cells [ 32 ]. While traditional approaches have their limitations, such as lacking sub-type specific cues and incomplete reprogramming, they have provided essential mechanistic insights into TF hierarchies and dynamics, allowing the discovery of pioneer factors and more effective cocktails [ 15 ]. 2.1. BAM factors in neuronal reprogramming Ectopic expression of achuete-scute homolog 1 (Ascl1), POU domain transcription factor (Brn2) and myelin transcription factor 1 like (Myt1l) transcription factors, together called BAM factors, is the most commonly used approach to study reprogramming to induce neuronal progenitor cells [ 33 ]. Ascl1, Brn2, and Myt1l are able to induce both morphological and physiological changes such as functional synapses and action potential in source cells to reprogram them into neonatal neurons [ 33 ]. While other combinations of TFs, as mentioned in Table 1 , can also give rise to neuronal progenitors, the BAM factors reprogrammed source cells to a higher degree of maturation and functionality [ 34 ]. Ascl1 is a basic helix-loop-helix DNA binding motif and is actively expressed in most neuronal progenitor cells [ 35 ]. Brn2 is expressed during early differentiation of a neuron throughout the neuroaxis and is downregulated as the cell matures, implying that it is important for maturation and stabilisation of neurons [ 36 ]. Myt1l is a zinc-finger DNA binding motif that is expressed in early post-mitotic neurons and contributes to tissue homogeneity and allows for rapid neuron formation in early brain development, implying it is also necessary for post-commitment growth [ 37 , 38 ]. Table 1. Collection of commonly used TF combinations for conversion to different subclasses of neurons. Source cell TF combination used Neuron sub-class and it’s characteristics Reprogramming Context References Human Fibroblast BAM NeuN-expressing neurons In-vitro [ 33 ] Human Astrocytes Sox2 shRNA-p53, BDNF-NOG Neuroblasts In-vivo/in-vitro [ 47 ] Human NG2 Glia Sox2, p75-2 Neuroblasts In-vitro [ 48 ] Mouse Astrocyte Pax6 Neonatal, immature neurons In-vivo [ 49 ] Human Vascular Pericytes BAM, Tlx3 miRNA-124 Cholinergic neurons In-vitro [ 50 ] Human cord blood cells Sox2, c-Myc Electro-physically active Glutamatergic and GABAergic neurons In-vitro [ 51 ] Mouse Fibroblasts Ascl1 Immature neurons In-vitro [ 35 ] Mouse Astrocytes Neurog2 Glutamatergic neurons In-vitro [ 52 ] Mouse astrocytes Ascl1, Lmx1a, Nurr1 Dopaminergic neurons In-vivo [ 53 ] Mouse astrocytes NeuroD1 Mature neurons In-vivo [ 54 ] Open in a new tab In-vitro studies showed that Ascl1 was the recruiting molecule for Brn2 and Myt1l and initiated chromatin changes [ 35 , 39 ]. This was backed by subsequent ChIP-seq, FAIRE-seq, RNA-seq etc studies which evaluated several molecular changes and global responses to the BAM factors [ 33 ]. It was observed that the factors were able to induce rapid and global transcriptional changes in the source fibroblasts[ 33 ]. Ascl1 was sufficient to induce a neuronic state in fibroblasts; however, cells were observed to be missing the expression of key physicochemical markers producing induced neural stem cells (iNSCs) [ 35 ]. Brn2 and Myt1l brought about subtle transcriptome changes which cascaded into upregulation and downregulation of many genes; however, they were not self-sufficient and required Ascl1 as an initiator [ 33 , 35 ]. Through studies [ 35 ], it was observed that without Brn2 and Myt1l, mice neurons were unable to differentiate properly, causing proliferation defects and thinning of the cortex [ 34 , 35 ] validating their presence to sustain the reprogramming. Furthermore, Zfp238, an important neuronal marker gene associated with Ascl1 was later identified to be activated by Myt1l [ 33 ]. Through computational techniques such as the determination of chromatin states using ChromHMM software in all cell types, it was also predicted that Ascl1 has better accessibility to binding sites in human dermal fibroblasts (NHDF) compared to normal human keratinocytes (NHEK) [ 33 ]. Thus, higher enrichment levels were identified in NHDFs, making it more efficient to reprogram NHDF to NPCs [ 33 ]. Additionally, human myoblasts showed similar enrichment levels as NHDF whereas human osteoblasts showed minimal enrichment [ 15 ]. Reprogramming of both cells showed similar patterns to NHDFs and NHEKs, respectively [ 15 ]. Additional literary review also revealed that there are 12 important TFs in neural development, however, none of the 12 factors could individually reprogram cells to neuronal progenitors [ 35 ]. Even after being coupled with Ascl1, multiple factors were not able to guarantee complete and safe reprogramming [ 35 ], hence validating the benefit of using the BAM factors. 2.2. Other transcription factors in neuronal reprogramming Other than the BAM factors, experiments have been conducted to reprogram NHDFs to dopaminergic neurons to build culture models to study PD [ 40 ]. Ascl1, Lmx1a and Nurr1, together called ALN factors, have been used to specifically conduct this subclass conversion [ 40 ]. Lmx1a engages in WNT and SHH signalling, determining floor-plate specification and Nurr1 directly regulates dopaminergic effector genes including TH, DAT and VMAT2 [ 41–43 ]. These TFs coordinate to activate subtype specific genes, triumphing over traditionally used cocktails [ 44 ]. Such subtype specific combinations are preferred and have been summarised in Table 2 . Table 2. Comparison between the different techniques employed for neuronal reprogramming on the basis of mechanisms basis, targets, advantages and disadvantages. Approach Mechanistic basis Targets for reprogramming Advantages Disadvantages References miRNA-based reprogramming Post-transcriptional repression of genes unrelated to neural fate and induction of brain-specific alternative splicing Brain-specific and neuron-specific miRNAs Enhances TF efficiency and neuron subtypes can be specifically made Overall lower efficiency as a standalone technique, challenges pertaining to delivery of the miRNA [ 55–59 , 81 ] TF + miRNA combinatorial Approach Complimentary activation of genes relating to neuronal fate and suppression of source cell’s fate and identity. Lineage specification genes for suppression and activation Higher efficiency than single method Challenges pertaining to safe and effective delivery [ 59 ] Small molecule-based reprogramming in vitro Epigenetic remodelling and small molecule interference to signalling pathways causing fate modulation HDACs, TGF- β and cAMP, along with other epigenetic remodelling molecules Non-genetic modes of reprogramming; scalable and reversible Stress-response elicited by MSCs; safety concerns [ 60 , 61 ] Small molecule-based reprogramming in vivo Modulation of developmental and related signalling pathways Notch, TGF- β, Wnt, BMP, SHH and other related pathways Avoids viral integration; higher survival duration Complicated chemical cocktails and limited midbrain specificity [ 64 ] Other small molecule cocktails Inhibition of lineage barriers Notch, TGF- β, Wnt, BMP, SHH and other related pathways Reduced chemical load and simpler cocktails; faster induction Limited midbrain specificity and limited subtype diversity [ 60 , 70 ] Intra-neuronal reprogramming Subtype switching within post-mitotic neurons Lineage specification genes for cortical layer identity Avoids proliferation stage; high survival in-vivo Limited to closely related neuronal subclasses only [ 72–74 ] CRISPR-activation Endogenous gene activation and function gain screening Activation of neuronal lineage TFs Precise targeting; high efficiency. Complicated delivery; off-target effects [ 76 , 77 ] CRISPR-based modulation of the mitochondria CRISPR- based targeting of mitochondrial genes and proteins for metabolic reprogramming Mitochondrial genome and cytoskeleton restructuring genes Address metabolic bottlenecks; enhanced yield. Mechanistic pathways still unknown completely. [ 76 , 80 ] Open in a new tab In another set of experiments [ 45 ] MEFs were noted to undergo similar changes while using ALN and BAM factors [ 45 ]. Other than ectopic expression, transfection of the mentioned TF is done using lentiviral vectors and inhibiting enzymes such as bone morphogenic blockers and adenylyl cyclase activator such as forskolin [ 46 ]. Other TF combinations used are indicated in Table 1 . 3. Novel approaches to neuronal reprogramming While overexpression of TFs is a common approach, it is limitedly used as an in-vitro approach. Delivery methods such as Retroviruses, Adeno-associated viruses (AAV) and Lentiviruses have also been used for targeted delivery of TFs in-vivo [ 47 , 48 ]. However, as research expands, other methods, as depicted in Figure 2 , have been developed for direct neuronal reprogramming, such as miRNAs, small molecules and CRISPR-based reprogramming [ 10 ]. Figure 2. Open in a new tab Graphical representation of different methods used for direct neuronal reprogramming. (Created with BioRender.com). 3.1. miRNA-based neuronal reprogramming While transcription factors control what gene is expressed, miRNAs are able to qualitatively control gene expression by targeting mRNA produced [ 55 ]. Knowing this has launched multiple investigations into miRNAs. The hsa-miR-9-5p/-3p has been noted to be responsible for neuronal fate induction and directly targets PTPB1, CoREST, SCP1 and BAF53a [ 56 , 57 ]. Similar brain specific miRNAs such as hsa-miR-124/hsa-miR-9-5p are known to promote neuronal cell fate by inducing brain-specific alternative splicing [ 58 ]. The overexpression of miR-9/9 and miR-124 was also studied and was able to re-purpose human fibroblasts to neurons [ 57 , 58 ]. A combinatorial approach, using both TFs and miRNAs was able to produce iDANs [ 59 ]. It was noted that 5p/miR34c-5p and miR-34b/c, when overexpressed with ASCL1 and NURR1 were more efficient than either approach used separately [ 59 ]. 3.2. Use of small molecules for neuronal chemical reprogramming While miRNAs show promise, the overall approach is expensive and time consuming. Hence small molecules which mimic the action of biological molecules are used. This technique is called chemical reprogramming [ 60 ]. Direct chemical reprogramming can be used for reprogramming various somatic cells to neuronal subclasses, such as its use for reprogramming human fibroblasts to Beta-3 tubulin neurons in-vitro [ 60 ]. This was achieved by treatment of cells with valproic acid (VPA), RepSox, forskolin, PKC inhibitor and a cocktail of HDAC inhibitors [ 61 ]. Other chemical approaches include using an environment of mercaptoethanol, dimethyl sulfoxide and butylated hydroxyanisole [ 61 , 62 ]. However, a limitation associated with this approach is that mesenchymal stem cells (MSCs) expressed stress response in addition to neural marker proteins such as TrkA, Tau and NSE, which is considered unsafe, if transplanted [ 62 , 63 ]. Chemical reprogramming also extends onto using small molecules to convert astrocytes into functional neurons in-vivo . This works by modifying neuro-differentiation signalling pathways [ 64 ] which include Notch signalling [ 65 ] and Activin signalling [ 66 ] to help in neuronal reprogramming. Other cycles targeted include Wnt signalling [ 67 ] and Retinoic Acid signalling [ 68 ] pathways to stimulate neurogenesis. Small molecules act as both antagonists and growth stimulators to aid in such modifications [ 18 ] as well as trigger genomic changes when an intermediate with an extra embryonic endoderm has formed [ 69 ]. However currently, small molecules are synthetically engineered to target epigenetic and signalling pathways, to not manipulate genes and increase efficiency [ 60 ]. The use of LDN193189, SB431542, TTNPB, thiazovivin, CHIR99021, VPA, DAPT, SAG, and purmorphamine to convert human astrocytes into functional neurons with a continuous action potential and morphological markers is a key example of this case [ 10 , 70 ]. This cocktail of small molecules activates NeuroD1, and other key TFs associated with neural cell fate commitment [ 70 ], while also supporting the survival of reprogrammed neurons for over a month in vivo [ 70 ]. However, while this strategy validates the scope of reprogramming as a therapeutic, the complexity of the protocol and time it requires urges for better strategies. Follow up studies [ 71 ] with simplified protocols, using DAPT, CHIR99021, SB431542, and LDN193189 have been developed to target Notch, glycogen synthase kinase 3, TGF-β, and BMP pathways [ 71 ]. This not only reduces the number of chemicals being used, but also simplifies the process, maintains efficacy and reduces induction time. However, this methodology is limited in producing GABAergic and glutamatergic neurons in the midbrain [ 71 ]. 3.3. Intra-neuronal reprogramming Additionally, intra-neuronal reprogramming is also possible. Neurons after early mitosis can be switched to a different subclass [ 72 ]. Early mitotic neurons and glial cells also share similar epigenetic features and the same embryonic layer, making them easy to reprogram in-vivo source cells [ 73 ]. Most notably, studies with Fezf2 TF treated mice neurons were done that observed IV spiny neurons converted to VB layer neurons when exposed to it [ 72 ]. Similar studies were also done on chimpanzees and significant layers of neuronal tissue were formed [ 74 ]. 3.4. CRISPR-based neuronal reprogramming Building on the trajectory of advancements in neuronal reprogramming, CRISPR technology has emerged as a powerful tool, expanding the ability to manipulate neural cell fate not just through precise transcription factor screening but also for genetic and transcriptomic modifications [ 75 ]. CRISPR-activation (CRISPR-a) has proven to be highly efficient, even while leveraging the current available ‘gain of function’ screens [ 76 ]. It predicted the use of Brn2 and Ngn1 to be highly efficient, which when tested showed an increased efficiency from 20% to 83% using Brn2 and Ngn1 instead of BAM factors [ 77 ]. Future proposals in different approaches to neuronal reprogramming include the utilisation of mitochondrial proteins [ 76 ]. Neurons rely on oxidative epigenetic modifications, such as oxidative phosphorylation [ 78 ] to increase the required mitochondrial activity [ 79 ]. Mitochondrial composition of astrocytes and glia have been compared with neurons to identify mismatches for further modifications [ 76 ]. While the methodology of conducting such studies is under evaluation, CRISPR-a has been employed to study the impact of the mitochondrial genome on neuronal reprogramming [ 76 ]. Targeting unique mitochondrial proteins specific to neurons, can help satiate metabolic needs of the induced neuronal cells [ 80 ]. CRISPR-a studies on the same concept have demonstrated that during the later stages of cytoskeleton restructuring, neuron-specific mitochondrial proteins are upregulated, and early induction of the same improves yield [ 76 ]. 4. Application of neuronal reprogramming for treatment of neurodegenerative diseases In vivo reprogramming serves significant advantages for the treatment of neurodegenerative diseases as it can be used as a tool to regenerate neurons and promote functional recovery, addressing limitations in current treatment strategies. Common approaches to the application of neuronal reprogramming have been summarized in Figure 3 . Figure 3. Open in a new tab Sources of cells used for clinical trials and potential treatment for neurodegenerative diseases. Both transplantation of in-vitro repurposed cells and in - vivo reprogramming are of great interest. (Created with BioRender.com). 4.1. Current strategies in Parkinsons’s and Alzheimer’s Disease treatment PD results from the loss of dopaminergic neurons [ 23 ], while AD is a progressive disorder primarily caused by the loss of cholinergic neurons, often due to the accumulation of beta-amyloid protein plaques [ 20 ]. Both PD and AD are complex disorders influenced by genetic and environmental factors. Consequently, a variety of therapies have been explored, including pharmacogenomics, stem cell therapies, and, more recently, direct reprogramming [ 82 ]. While pharmacogenomic therapies can alleviate the symptoms, they fail to treat the condition [ 27 , 82 , 83 ]. Stem cell therapies face limitations due to the restricted regenerative capacity of the CNS, outweighing its promise [ 27 , 83 ]. Transplantation of iPSCs and ESCs into the putamen to reduce dopamine and acetylcholine loss is a common approach. Studies [ 83–90 ] have demonstrated the compatibility between host cells and cryopreserved ESCs (e.g. MSK-DA01). This has been validated by preclinical studies which show that human-grade iPSCs have high efficiency in treating brain lesions and no signs of tumorigenicity in rats [ 26 , 86 ]. Direct in-vivo neuronal reprogramming offers an alternative, bypassing the current need for transplantation and avoiding immune rejection [ 91–93 ]. In 2010, BAM factors were discovered to directly convert mouse embryonic fibroblasts (MEFs) into functional neurons in-vitro [ 94 , 95 ]. This breakthrough has paved the way for direct reprogramming as a potential therapy for Parkinson’s and Alzheimer’s diseases. 4.2. Astrocyte reprogramming as a potential therapy for neurodegenerative disorders More recently, focus has shifted to astrocyte-to-neuron reprogramming, as it holds significant promise due to the proximity of these cells and their shared precursor. Astrocytes are complex glial cells which manage toxin accumulations near synapses and help in maintaining transmitter homeostasis [ 94 , 96 ]. They possess proliferative potential and lineage proximity, making them ideal candidates for reprogramming to neurons [ 33 ]. Astrocyte reprogramming to neural progenitors has been studied using TFs and miRNAs. Direct reprogramming bypasses the issue of teratoma formation, as faced by iPSCs, making this approach a better candidate for therapeutics [ 40 ]. Recent studies have demonstrated the use of TF cocktails, specifically the Ascl1, Nurr1, and Lmx1a combination to induce dopaminergic neurons from MEFs and human fibroblasts with minimal teratoma risks [ 40 ]. Approaches with single TFs like SOX2 have also successfully converted NG2 glia into double cortin-positive neurons [ 97 ], while Ascl1 has reprogrammed astrocytes into neurons in the mouse midbrain, exhibiting neuronal markers and action potentials [ 98 ]. Some studies also observe that SOX2, in combination with Nurr1, Lmx1a, Foxa2, and valproic acid, is capable of reprogramming mouse striatal neurons, hinting at the potential of a complete brain redesign [ 7 ]. Mouse models of PD treated with SOX2 also showed greater restoration in motor behaviour through CRISPR-mediated reprogramming of astrocytes, suggesting its viability as an autologous therapy for PD [ 99 ]. In recent trials [ 96 , 100–104 ] NeuroD1 has emerged as pivotal TF for astrocyte-to-neuron in-situ conversion [ 104 , 105 ] with minimal neuroinflammation and reduced reactive microglia [ 1 ]. Meta studies have shown that miRNA-based clinical trials have also contributed valuable insights. Brain-specific miRNAs, such as miRNA-124a and miRNA-9, are known to be critical for cell fate determination and neurogenesis [ 81 ]. In one specific trial, miRNA-124 was paired with NeuroD2 and outperformed individual usage of each component [ 58 , 103 ]. The exploration of tissue nano-transfection as an approach to reprogramming has also revealed that transforming fibroblasts into vascular cells using the EFF TF group consisting of Etv2, Foxc2 and Fli1 is effective [ 106 ]. This strategy has shown high recovery rate for irreversible brain ischemia and strokes [ 106 ]. Trials using Ptbp1 and CRISPR-CasRx technology in mice has also demonstrated high efficiency causing the study to advance to Phase II/III trials [ 103 ]. However, concerns about insertional mutagenesis and chromosomal instability persist [ 107 ]. 5. Challenges and current progress Neuronal reprogramming comes with its fair share of challenges and roadblocks which cause hindrance with its development as an autologous therapy for neurodegenerative disorders. 5.1. Molecular and physiological barriers to reprogramming efficiency The morphological and physicochemical similarities between NHDFs and NPCs raises the question, whether certain cell types are more conducive to reprogramming than others. This arises from molecular similarities such as fibroblasts showing high cell turnover and myoblasts existing as satellite cells for muscle regeneration [ 108 ]. Additionally, a contributing factor to reprogramming may be unique molecular patterns of the cells, such as the coordinated expression of certain niche gene families [ 56 ]. This observation leads to a hypothesis, similar to the “seed and soil theory” in cancer biology, suggesting that certain cell types might be inherently more favourable to reprogramming [ 109 ]. Unlike cardiomyocytes, which have shown to achieve electrophysiological compatibility with native cells in a tissue microenvironment, reprogrammed neuronal progenitors struggle to integrate with surrounding cells, which may be due to intermediate phenotypes and brain region-specific sub-classes [ 40 ]. Reprogrammed neurons often resemble neonatal cells rather than mature somatic cells with synaptic connectivity, axonal targeting and sub-type specification, further complicating compatibility and sometimes leading to reversion to their original source cell type [ 110 ]. Mechanistically, reprogramming efficiency is strongly influenced by chromatin accessibility, histone modification and DNA methylation which affects chromatin dynamics with neuronal fate enhancers [ 31 , 111 ]. These molecular aspects of a cell often act as barriers to reprogramming and cause retention of the source cell’s identity [ 31 , 112 ]. DNA methylation can restrict the binding of TF and in turn restricts reprogramming [ 113 ]. In addition to this, metabolic state can contribute significantly to the reprogramming outcomes [ 114 ]. For example, fibroblasts rely on glycolysis while mature neurons rely on oxidative phosphorylation [ 114 ]. This discrepancy reflects during incomplete metabolic reprogramming where the incompatibility in cell’s metabolic state can cause ROS accumulation, stress response activation and incomplete maturation [ 114 ]. These factors are likely to contribute to functional incompatibility with native tissue. In addition to this, mechanisms are further complicated by region-specific cues such as ECM composition, local activity-dependent signalling and glial composition. These effects have been further detailed upon [ 115 , 116 ]. 5.2. Challenges in astrocyte-to-neuron reprogramming specific to surgical applications While reprogramming efficiency is continuously being improved using different techniques, the rates remain insufficient for clinical applications [ 18 ]. Additionally, the lack of reliable non-viral delivery systems poses multiple health risks to at-risk patients [ 18 ]. Environmental factors and regional differences in transplantation sites have been shown to influence reprogramming efficiency [ 117 , 118 ]. Thus, understanding brain microenvironments is crucial for successful astrocyte reprogramming, in turn necessitating further research into brain region mapping and region-specific factors. Targeting specific neuron sub-classes and identifying optimal transplantation locations are also essential to improving reprogramming efficiency[ 118 ]. For surgical applications and graft-based therapies, situational challenges such as oxidative stress, angiogenesis, and the use of certain medications have shown to reduce the efficiency of in-vivo reprogramming and lower graft acceptance rates [ 119 ]. Inflammatory environments, common in Parkinson’s patients, exaggerate these issues, further reducing efficiency [ 120 ]. 5.3. Challenges as presented by clinical trials Clinical studies have highlighted that one of the major challenges faced is reaching a significant number of cells required to treat PD and AD [ 103 , 121 ]. For instance, on study reported the requirement of approximately 100,000 dopaminergic neurons to bring about a therapeutic effect in PD models [ 122 ]. Hence, reprogramming to reach such a large quantity of cells in-vitro remains to be a great research interest [ 122 ]. Additionally, clinical trials have demonstrated metabolic differences between astrocytes, fibroblasts, and neurons and their impact on reprogramming efficiency [ 104 , 122 ]. Astrocytes and fibroblasts rely on glycolysis and beta-oxidation, whereas neurons depend on oxidative phosphorylation [ 123 ]. Such discrepancies may be affecting reprogramming efficiency in-situ. 5.4. Regional and species heterogeneity as a translational barrier A critical limitation that is insufficiently addressed during development of such therapies is the consideration of regional and species-specific heterogeneity. The brain displays diversity in terms of neuronal subtype, composition, glial distribution, synaptic architecture and epigenetic landscape which causes heterogeneities in regions, chemical microenvironments and the regulation of genes [ 124 ]. Region-specific identities are known to be tightly controlled via transcriptional and chromatin programs [ 124 , 125 ]. We know this from the astrocytes of different brain regions displaying distinct transcriptomic profiles [ 115 ]. Additionally, when exposed to neurogenic TFs, they displayed varying responsivity, suggesting varying conversion efficiency as well[ 115 , 126 ]. Most in-vivo studies are validated on rodent brains. This may be causing discrepancies as single-cell data suggests that rodent and human glial cells diverge massively in terms of inflammatory signalling, metabolic regulation and chromatin organization, wherein mouse astrocytes are more permissive to epigenetic changes [ 127 , 128 ]. Human astrocytes being larger, more complex and have unique transcriptomic profiles which are not epitomized in rodent models [ 127 ]. Interspecies differences such as neurogenic potential, ion channel density and neuroblast marker expression, may alter TF activity and chromatin remodelling dynamics, causing discrepancies we see in results [ 128 ]. On the other hand, in-vitro studies done using cell lines lack the context of external cues such as mechanical shear, ECM composition and cytokine gradients in tissue microenvironment and the perspective of multicellularity [ 129 , 130 ]. Region specific phenotypes further complicate the results of in-vitro and in- vivo studies for any generalisation [ 116 ]. These concepts point out that acknowledging regional and species-specific heterogeneities may provide us more context into translating the proof-of-concepts to actual clinical results. 5.5. Conflicting results in astrocyte-to-neuron conversion There have been contrasting results regarding the source of reprogrammed neurons, complicating the field. These arise from unreliable lineage detection systems, complicating our current understanding of the process. Common lineage-tracing methods include lineage-tracing mice models [ 131 ], BrdU/Edu-based labelling, time-lapse in-vivo imaging, and scRNA sequencing [ 131 , 132 ]. Questions surround newly generated neurons and whether they arise from transdifferentiated glial cells or pre-existing neurons challenge the reliability of current techniques. For instance, during AAV-mediated NeuroD1 expression, GFAP-reporter-labelled neurons could not be traced back to resident astrocytes which were used as the source cells [ 133 ]. Lineage-tracing studies also report conflicting observations. Some evidence supports astrocyte-to-neuron conversion while others challenge the same, such as PTBP1 studies using the Aldh1l1-CreERT2 method, which failed to replicate these results and further went on to suggest that newly generated neurons arise from preexisting neurons [ 133 , 134 ]. 6. Conclusion Despite these challenges, the field has made significant progress toward therapeutic applications. The main advantage of in-vivo direct reprogramming lies in the fact that we can regenerate neurons directly from a patient’s own cells without the need for transplantations, theoretically eliminating immunosuppressive medication requirements. This approach can help reduce mortality rates associated to brain ischemia, stroke and traumatic injuries while also being a solution to treating neurodegenerative disorders. An additional therapeutic advantage of this approach addresses scar tissue formation by reactive glial cells, which can be treated using direct neuronal reprogramming. Based on the current status of neuronal reprogramming, several inferences emerge that can influence its future applications. The reduced reprogramming efficiency remains one of the most critical challenges. This suggests that we need to invest more time and resources into studying combinatorial approaches targeting multiple reprogramming pathways. As mentioned before, energy insufficiency in reprogrammed cells may be a contributing factor to reduced efficiency and may also be linked to reprogramming pathways and the coordinated expression of niche gene families. The controversies surrounding lineage tracing imply that current technology and protocols leave room for error. While this field requires innovative solutions, it also requires standardized validation protocols. The integration of reliable and safe delivery systems, improved TF combinations, and strategies to tackle environmental variability in patients will likely assist in enhancing the clinical viability of neuronal reprogramming. Ultimately, translation of neuronal reprogramming into a clinical therapeutic will require working on not just the technical challenges pertaining to studying developmental biology, but also processes of integration, maturation, and long-term survival in neural environments. 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