Have a personal or library account? Click to login
Neuronal Transdifferentiation in Humans: Protocols for Monocytes Conversion into Neuronal-Like Cells with Small Molecules Cover

Neuronal Transdifferentiation in Humans: Protocols for Monocytes Conversion into Neuronal-Like Cells with Small Molecules

Open Access
|Jan 2026

References

  1. Aguilera-Castrejon A, Pasantes-Morales H, Montesinos JJ et al. (2017) Improved proliferative capacity of NP-Like cells derived from human mesenchymal stromal cells and neuronal transdifferentiation by small molecules. Neurochem Res 42:415–427. https://doi.org/10.1007/s11064-016-2086-7
  2. Ambasudhan R, Talantova M, Coleman R et al. (2011) Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell Stem Cell 9:113–118. https://doi.org/10.1016/j.stem.2011.07.002
  3. Bellon A, Wegener A, Lescallette AR et al. (2018) Transdifferentiation of human circulating monocytes into neuronal-like cells in 20 days and without reprograming. Front Mol Neurosci 11:323. https://doi.org/10.3389/fnmol.2018.00323
  4. Bueno C, Martínez-Morga M, García-Bernal D et al. (2021) Differentiation of human adult-derived stem cells towards a neural lineage involves a dedifferentiation event prior to differentiation to neural phenotypes. Sci Rep 11:12034. https://doi.org/10.1038/s41598-021-91566-9
  5. Caiazzo M, Dell'Anno MT, Dvoretskova E et al. (2011) Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476:224–227. https://doi.org/10.1038/nature10284
  6. Chan CC, Wong AK, Liu J et al. (2007) ROCK inhibition with Y27632 activates astrocytes and increases their expression of neurite growth-inhibitory chondroitin sulfate proteoglycans. Glia 55:369–384. https://doi.org/10.1002/glia.20466
  7. Chu X, Wang J (2021) Dynamics and pathways of chromosome structural organizations during cell transdifferentiation. JACS Au 2:116–127. https://doi.org/10.1021/jacsau.1c00416
  8. Cieślar-Pobuda A, Rafat M, Knoflach V et al. (2016) Human induced pluripotent stem cell differentiation and direct transdifferentiation into corneal epithelial-like cells. Oncotarget 7:42314–42329. https://doi.org/10.18632/oncotarget.9791
  9. Das M, Pethe P (2021) Differential expression of retinoic acid alpha and beta receptors in neuronal progenitors generated from human embryonic stem cells in response to TTNPB (a retinoic acid mimetic). Differentiation 121:13–24. https://doi.org/10.1016/j.diff.2021.08.001
  10. Descoteaux M, Sunnerberg JP, Brady DD et al. (2022) Feedback-controlled dynamics of neuronal cells on directional surfaces. Biophys J 121:769–781. https://doi.org/10.1016/j.bpj.2022.01.020
  11. Fernandes GS, Singh RD, De D et al. (2023) Strategic application of epigenetic regulators for efficient neuronal reprogramming of human fibroblasts. Int J Stem Cells 16:156–167. https://doi.org/10.15283/ijsc22183
  12. Gao L, Guan W, Wang M et al. (2017) Direct generation of human neuronal cells from adult astrocytes by small molecules. Stem Cell Rep 8:538–547. https://doi.org/10.1016/j.stemcr.2017.01.014
  13. Gascón S, Masserdotti G, Russo GL et al. (2017) Direct neuronal reprogramming: Achievements, hurdles, and new roads to success. Cell Stem Cell 21:18–34. https://doi.org/10.1016/j.stem.2017.06.011
  14. Ghosh N, Santoni D, Saha I et al. (2024) Predicting transcription factor binding sites with deep learning. Int J Mol Sci 2:4990. https://doi.org/10.3390/ijms25094990
  15. Gupta V, Gharai PK, Kar C et al. (2024) Ratiometric fluorescent probe promotes trans-differentiation of human mesenchymal stem cells to neurons. ACS Chem Neurosci 15:222–229. https://doi.org/10.1021/acschemneuro.3c00630
  16. Gupta V, Mahata T, Roy R et al. (2022) Discovery of imidazole-based GSK-3β inhibitors for transdifferentiation of human mesenchymal stem cells to neurons: A potential single-molecule neurotherapeutic foresight. Front Mol Neurosci 15:1002419. https://doi.org/10.3389/fnmol.2022.1002419
  17. Gurvich N, Tsygankova OM, Meinkoth JL et al. (2004) Histone deacetylase is a target of valproic acid-mediated cellular differentiation. Cancer Res 64:1079–1086. https://doi.org/10.1158/0008-5472.can-03-0799
  18. Handy DE, Castro R, Loscalzo J (2011) Epigenetic modifications: Basic mechanisms and role in cardiovascular disease. Circulation 123:2145–2156. https://doi.org/10.1161/CIRCULATIONAHA.110.956839
  19. Han JY, Lee EH, Kim SM et al. (2023) Efficient generation of dopaminergic neurons from mouse ventral midbrain astrocytes. Biomol Ther (Seoul) 31:264–275. https://doi.org/10.4062/biomolther.2022.140
  20. Hao Y, Creson T, Zhang L et al. (2004) Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J Neurosci 24:6590–6599. https://doi.org/10.1523/JNEUROSCI.5747-03.2004
  21. Herdy J, Schafer S, Kim Y et al. (2019) Chemical modulation of transcriptionally enriched signaling pathways to optimize the conversion of fibroblasts into neurons. Elife 8:e41356. https://doi.org/10.7554/eLife.41356
  22. Hou P, Li Y, Zhang X et al. (2013) Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science 341:651–654. https://doi.org/10.1126/science.1239278
  23. Hoveizi E, Mohammadi T, Moazedi AA et al. (2018) Transplanted neural-like cells improve memory and alzheimer-like pathology in a rat model. Cytotherapy 20:964–973. https://doi.org/10.1016/j.jcyt.2018.03.036
  24. Hu W, Qiu B, Guan W et al. (2015) Direct conversion of normal and Alzheimer's disease human fibroblasts into neuronal cells by small molecules. Cell Stem Cell 17:204–212. https://doi.org/10.1016/j.stem.2015.07.006
  25. Hybiak J, Jankowska K, Machaj F et al. (2020) Reprogramming and transdifferentiation - Two key processes for regenerative medicine. Eur J Pharmacol 882:173202. https://doi.org/10.1016/j.ejphar.2020.173202
  26. Khazaei N, Rastegar-Pouyani S, O'Toole N et al. (2018) Regulating the transcriptomes that mediate the conversion of fibroblasts to various nervous system neural cell types. J Cell Physiol 233:3603–3614. https://doi.org/10.1002/jcp.26221
  27. Kim EJ, Leung CT, Reed RR et al. (2007) In vivo analysis of Ascl1 defined progenitors reveals distinct developmental dynamics during adult neurogenesis and gliogenesis. J Neurosci 27:12764–12774. https://doi.org/10.1523/jneurosci.3178-07.2007
  28. Kiselev IS, Kulakova OG, Boyko AN et al. (2021) DNA methylation as an epigenetic mechanism in the development of multiple sclerosis. Acta Naturae 13:45–57. https://doi.org/10.32607/actanaturae.11043
  29. Koshy A, Mathieux E, Stüder F et al. (2022) Synergistic activation of RARβ and RARγ nuclear receptors restores cell specialization during stem cell differentiation by hijacking RARα-controlled programs. Life Science Alliance 6:e202201627. https://doi.org/10.26508/lsa.202201627
  30. Lee J, Taylor CA, Barnes KM et al. (2019) A Myt1 family transcription factor defines neuronal fate by repressing non-neuronal genes. Elife 8:e46703. https://doi.org/10.7554/eLife.46703
  31. Li X, Fang P, Yang WY et al. (2017) Mitochondrial ROS, uncoupled from ATP synthesis, determine endothelial activation for both physiological recruitment of patrolling cells and pathological recruitment of inflammatory cells. Can J Physiol Pharmacol 95:247–252. https://doi.org/10.1139/cjpp-2016-0515
  32. Liu D, Rychkov G, Al-Hawwas M et al. (2020) Conversion of human urine-derived cells into neuron-like cells by small molecules. Mol Biol Rep 47:2713–2722. https://doi.org/10.1007/s11033-020-05370-1
  33. Mahony S, Mazzoni EO, McCuine S et al. (2011) Ligand-dependent dynamics of retinoic acid receptor binding during early neurogenesis. Genome Biol 12:R2. https://doi.org/10.1186/gb-2011-12-1-r2
  34. Masserdotti G, Gascón S, Götz M (2016) Direct neuronal reprogramming: Learning from and for development. Development 143:2494–2510. https://doi.org/10.1242/dev.092163
  35. Mertsch S, Krämer OH (2017) The interplay between histone deacetylases and rho kinases is important for cancer and neurodegeneration. Cytokine Growth Factor Rev 37:29–45. https://doi.org/10.1016/j.cytogfr.2017.05.006
  36. Mishra A, Mohan KV, Nagarajan P et al. (2020) Peripheral blood-derived monocytes show neuronal properties and integration in immune-deficient rd1 mouse model upon phenotypic differentiation and induction with retinal growth factors. Stem Cell Res Ther 11:412. https://doi.org/10.1186/s13287-020-01925-y
  37. Mitchell AJ, Roediger B, Weninger W (2014) Monocyte homeostasis and the plasticity of inflammatory monocytes. Cell Immunol 291:22–31. https://doi.org/10.1016/j.cellimm.2014.05.010
  38. Ninomiya I, Kanazawa M, Koyama A et al. (2019) Highly efficient direct conversion of human monocytes into neuronal cells using a small molecule combination. bioRxiv. https://doi.org/10.1101/803254
  39. Pan Z, Oh J, Huang L et al. (2020) The combination of forskolin and VPA Increases gene expression efficiency to the hypoxia/neuron-specific system. Ann Transl Med 8:933. https://doi.org/10.21037/atm-20-3871
  40. Paudel P, Gharai PK (2025) Dual-function fluorescent probes for neuronal trans-differentiation: A promising therapeutic strategy in neuroregenerative research. ACS Chem Neurosci 16:2561–2563. https://doi.org/10.1021/acschemneuro.5c00367
  41. Paudel P, Kumarchinchole RP, Gharai PK (2025) Can oxytocin neuropeptide promote human mesenchymal stem cells to neuron conversion? A novel approach in future neurotherapeutic research. ACS Chem Neurosci 16:2753–2755. https://doi.org/10.1021/acschemneuro.5c00520
  42. Podleśny-Drabiniok A, Sobska J, de Lera AR et al. (2017) Distinct retinoic acid receptor (RAR) isotypes control differentiation of embryonal carcinoma cells to dopaminergic or striatopallidal medium spiny neurons. Sci Rep 7:13671. https://doi.org/10.1038/s41598-017-13826-x
  43. Qin H, Zhao A, Ma K et al. (2018) Chemical conversion of human and mouse fibroblasts into motor neurons. Sci China Life Sci 61:1151–1167. https://doi.org/10.1007/s11427-018-9359-8
  44. Qin H, Zhao AD, Sun ML et al. (2020) Direct conversion of human fibroblasts into dopaminergic neuron-like cells using small molecules and protein factors. Mil Med Res 7:52. https://doi.org/10.1186/s40779-020-00284-2
  45. Rangasamy SB, Dasarathi S, Nutakki A et al. (2021) Stimulation of dopamine production by sodium benzoate, a metabolite of cinnamon and a food additive. J Alzheimers Dis Rep 5:295–310. https://doi.org/10.3233/ADR-210001
  46. Sharif A, Prevot V (2012) Isolation and culture of human astrocytes. Methods Mol Biol 814:137–151. https://doi.org/10.1007/978-1-61779-452-0_11
  47. Shi CJ, Lian JJ, Zhang BW et al. (2023) TGFβR-1/ALK5 inhibitor RepSox induces enteric glia-to-neuron transition and influences gastrointestinal mobility in adult mice. Acta Pharmacol Sin 44:92–104. https://doi.org/10.1038/s41401-022-00932-4
  48. Sorraksa N, Kaokaen P, Kunhorm P et al. (2024) Rapid induction of dopaminergic neuron-like cells from human fibroblasts by autophagy activation with only 2-small molecules. 3 Biotech 14:115. https://doi.org/10.1007/s13205-024-03957-0
  49. Takayama Y, Wakabayashi T, Kushige H et al. (2017) Brief exposure to small molecules allows induction of mouse embryonic fibroblasts into neural crest-like precursors. FEBS Lett 591:590–602. https://doi.org/10.1002/1873-3468.12572
  50. Tanabe K, Ang CE, Chanda S et al. (2018) Transdifferentiation of Human adult peripheral blood T cells into neurons. Proc Natl Acad Sci USA 115:6470–6475. https://doi.org/10.1073/pnas.1720273115
  51. Tarsa L, Goda Y (2002) Synaptophysin regulates activity-dependent synapse formation in cultured hippocampal neurons. Proc Natl Acad Sci USA 99:1012–1016. https://doi.org/10.1073/pnas.022575999
  52. Thompson R, Casali C, Chan C (2019) Forskolin and IBMX Induce neural transdifferentiation of MSCs through downregulation of the NRSF. Sci Rep 9:2969. https://doi.org/10.1038/s41598-019-39544-0
  53. Vierbuchen T, Ostermeier A, Pang ZP et al. (2010) Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463:1035–1041. https://doi.org/10.1038/nature08797
  54. Wang X, Duan C, Li Y et al. (2022) Sodium butyrate reduces overnutrition-induced microglial activation and hypothalamic inflammation. Int Immunopharmacol 111:109083. https://doi.org/10.1016/j.intimp.2022.109083
  55. Wang G, Zhang D, Qin L et al. (2024) Forskolin-driven conversion of human somatic cells into induced neurons through regulation of the cAMP-CREB1-JNK signaling. Theranostics 14:1701–1719. https://doi.org/10.7150/thno.92700
  56. Wei DC, Morrison EH (2024) Histology, astrocytes. In: StatPearls. StatPearls Publishing, Treasure Island, FL. http://www.ncbi.nlm.nih.gov/books/NBK545142/. Accessed 25 July 2024
  57. Wei Z, Sakamuru S, Zhang L et al. (2019) Identification and profiling of environmental chemicals that inhibit the TGFβ/SMAD signaling pathway. Chem Res Toxicol 32:2433–2444. https://doi.org/10.1021/acs.chemrestox.9b00228
  58. Xu G, Wu F, Gu X et al. (2019) Direct conversion of human urine cells to neurons by small molecules. Sci Rep 9:16707. https://doi.org/10.1038/s41598-019-53007-6
  59. Yamanaka S (2009) Elite and stochastic models for induced pluripotent stem cell generation. Nature 460:49–52. https://doi.org/10.1038/nature08180
  60. Yang J, Cao H, Guo S et al. (2020) Small molecular compounds efficiently convert human fibroblasts directly into neurons. Mol Med Rep 22:4763–4771. https://doi.org/10.3892/mmr.2020.11559
  61. Yang Y, Chen R, Wu X et al. (2019) Rapid and efficient conversion of human fibroblasts into functional neurons by small molecules. Stem Cell Rep 13:862–876. https://doi.org/10.1016/j.stemcr.2019.09.007
  62. Zhang QJ, Li JJ, Lin X et al. (2017) Modeling the Phenotype of spinal muscular atrophy by the direct conversion of human fibroblasts to motor neurons. Oncotarget 8:10945–10953. https://doi.org/10.18632/oncotarget.14641
  63. Zhang L, Yin JC, Yeh H et al. (2015) Small molecules efficiently reprogram human astroglial cells into functional neurons. Cell Stem Cell 17:735–747. https://doi.org/10.1016/j.stem.2015.09.012
  64. Zhao Y, Zhao T, Guan J et al. (2015) A XEN-like state bridges somatic cells to pluripotency during chemical reprogramming. Cell 163:1678–1691. https://doi.org/10.1016/j.cell.2015.11.017
Language: English
Submitted on: Aug 13, 2025
|
Accepted on: Oct 2, 2025
|
Published on: Jan 26, 2026
In partnership with: Paradigm Publishing Services
Publication frequency: 1 issue per year

© 2026 Kornelia Jankowska, Saeid Ghavami, Jolanta Hybiak, Marek J. Łos, published by Hirszfeld Institute of Immunology and Experimental Therapy
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.