Neurotoxins Induced Toxicogenomic Patterns on Human Induced Pluripotent Stem Cell based Microphysiological System
Main Article Content
Abstract
The traditional testing requirements for both adult and developmental neurotoxicity evaluations are based on in vivo animal models while the neurotoxic risks associated with molecules or vaccines is mainly determined by neurobehavioral and neuropathological effects in the experimental model chosen. The poor correlation between preclinical in vitro or in vivo data (non-human) with the real time clinical effects leading to severe progressive adverse events is a major concern in general. The employed bioinformatics search tools helped us to short list the affected common genes in neurotoxicity induced by viral, bacterial infections and cytokine storms. Here, we used our group characterized human induced Pluripotent Stem Cell (hiPSC) system developed as an in vitro microphysiological model to record phenotype and genotype perturbations when treated with selected known representative neurotoxins like TEA, Tetanus toxin, MSG, Dopamine, Bungarotoxin etc. The objective was to assess the application qualification of the novel in vitro model that yields human relevant readouts. The recorded phenotype perturbations were barcoded with SOD, BAX, HDAC1, TNFalpha, MAPK14 like gene expressions in generating in vitro patterns to correlate the human functional toxicogenomics information. We showed hiPSC system to be phenotypically responsive and genotypically reactive when treated with neurotoxins. Out of 7 gene expression data sets generated, SOD and BAX were recorded to be downregulated at all the micro-conditions created in the hiPSC system while HDAC was consistently upregulated except in Dopamine treated system. The bioinformatics analysis performed on the selected genes gave insight into their roles in disease specific signalling pathways like JAK-STAT, TNF, Neurotrophin etc. We report configured hiPSC system suitability as an in vitro human surrogate platform/model in generating toxicogenomics signatures to support prediction on the test material in any assay system developed on this well characterized microphysiological base.
Keywords: Human microphysiological system, neurotoxicity, hiPSC, phenomics, in vitro prediction mode
Keywords:
Human microphysiological system, neurotoxicity, hiPSC, phenomics, in vitro prediction mode
Article Details
How to Cite
DASARI, Vasanthi et al.
Neurotoxins Induced Toxicogenomic Patterns on Human Induced Pluripotent Stem Cell based Microphysiological System.
Medical Research Archives, [S.l.], v. 10, n. 10, oct. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3202>. Date accessed: 21 nov. 2024.
doi: https://doi.org/10.18103/mra.v10i10.3202.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Popoff MR, Poulain B. Bacterial toxins and the nervous system: neurotoxins and multipotential toxins interacting with neuronal cells. Toxins (Basel). Apr 2010;2(4):683-737.
doi: 10.3390/toxins2040683
2. Feldman RG. Occupational and environmental neurotoxicology. Lippincott-Raven; 1999:xix, 500 p.
3. Dubovicky M, Kovacovsky P, Ujhazy E, Navarova J, Brucknerova I, Mach M. Evaluation of developmental neurotoxicity: some important issues focused on neurobehavioral development. Interdiscip Toxicol. Dec 2008;1(3-4):206-10.
doi : 10.2478/v10102-010-0042-y
4. Plunkett LM. Developmental neurotoxicity of industrial chemicals. Lancet. Mar 10 2007;369(9564):821.
doi: 10.1016/S0140-6736(07)60396-1
5. Saunders NR, Dziegielewska KM. Developmental neurotoxicity of industrial chemicals. Lancet. Mar 10 2007;369(9564):821.
doi: 10.1016/S0140-6736(07)60397-3
6. Grandjean P, Landrigan PJ. Developmental neurotoxicity of industrial chemicals. Lancet. Dec 16 2006;368(9553):2167-78.
doi: 10.1016/S0140-6736(06)69665-7
7. Harry GJ, Billingsley M, Bruinink A, et al. In vitro techniques for the assessment of neurotoxicity. Environ Health Perspect. Feb 1998;106 Suppl 1:131-58.
doi: 10.1289/ehp.98106s1131
8. Kaur P, Aschner M, Syversen T. Biochemical factors modulating cellular neurotoxicity of methylmercury. J Toxicol. 2011;2011:721987.
doi: 10.1155/2011/721987
9. Niu N, Wang L. In vitro human cell line models to predict clinical response to anticancer drugs. Pharmacogenomics. 2015;16(3):273-85.
doi: 10.2217/pgs.14.170
10. Stoddart MJ. Cell viability assays: introduction. Methods Mol Biol. 2011;740:1-6.
doi: 10.1007/978-1-61779-108-6_1
11. Adan A, Kiraz Y, Baran Y. Cell Proliferation and Cytotoxicity Assays. Curr Pharm Biotechnol. 2016;17(14):1213-1221. doi: 10.2174/1389201017666160808160513
12. Lin L, Desai R, Wang X, Lo EH, Xing C. Characteristics of primary rat microglia isolated from mixed cultures using two different methods. J Neuroinflammation. May 8 2017;14(1):101.
doi: 10.1186/s12974-017-0877-7
13. Shin EJ, Tran HQ, Nguyen PT, et al. Role of Mitochondria in Methamphetamine-Induced Dopaminergic Neurotoxicity: Involvement in Oxidative Stress, Neuroinflammation, and Pro-apoptosis-A Review. Neurochem Res. Jan 2018;43(1):66-78.
doi: 10.1007/s11064-017-2318-5
14. Sahu MP, Nikkila O, Lagas S, Kolehmainen S, Castren E. Culturing primary neurons from rat hippocampus and cortex. Neuronal Signal. Jun 2019;3(2):NS20180207.
doi: 10.1042/NS20180207
15. Salazar IL, Mele M, Caldeira MV, et al. Preparation of Primary Cultures of Embryonic Rat Hippocampal and Cerebrocortical Neurons. Bio Protoc. Sep 20 2017;7(18):e2551.
doi: 10.21769/BioProtoc.2551
16. Luz AL, Tokar EJ. Pluripotent Stem Cells in Developmental Toxicity Testing: A Review of Methodological Advances. Toxicol Sci. Sep 1 2018;165(1):31-39.
doi: 10.1093/toxsci/kfy174
17. Romito A, Cobellis G. Pluripotent Stem Cells: Current Understanding and Future Directions. Stem Cells Int. 2016;2016:9451492.
doi:10.1155/2016/9451492
18. Tukker AM, Wijnolts FMJ, de Groot A, Westerink RHS. Human iPSC-derived neuronal models for in vitro neurotoxicity assessment. Neurotoxicology. Jul 2018; 67:215-225.
doi: 10.1016/j.neuro.2018.06.007
19. Kapalczynska M, Kolenda T, Przybyla W, et al. 2D and 3D cell cultures - a comparison of different types of cancer cell cultures. Arch Med Sci. Jun 2018;14(4):910-919.
doi: 10.5114/aoms.2016.63743
20. Park IH, Arora N, Huo H, et al. Disease-specific induced pluripotent stem cells. Cell. Sep 5 2008;134(5):877-86.
doi: 10.1016/j.cell.2008.07.041
21. Moretti A, Bellin M, Welling A, et al. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med. Oct 7 2010;363(15):1397-409.
doi: 10.1056/NEJMoa0908679
22. Ebert AD, Yu J, Rose FF, Jr., et al. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature. Jan 15 2009;457(7227):277-80.
doi: 10.1038/nature07677
23. Dasari V, Bolimera P, Krishna Gorthi L, Dravida S. In Vitro Profiling of Application Ready Human Surrogate Primary Progenitor Stromal Cell Fractions. Archives of Clinical and Biomedical Research. 2022;06(03)
doi: 10.26502/acbr.50170266
24. Huang L, Huang QY, Huang HQ. The evidence of HeLa cell apoptosis induced with tetraethylammonium using proteomics and various analytical methods. J Biol Chem. Jan 24 2014;289(4):2217-29.
doi: 10.1074/jbc.M113.515932
25. Deshane J, Garner CC, Sontheimer H. Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2. J Biol Chem. Feb 7 2003;278(6):4135-44.
doi: 10.1074/jbc.M205662200
26. DeBin JA, Maggio JE, Strichartz GR. Purification and characterization of chlorotoxin, a chloride channel ligand from the venom of the scorpion. Am J Physiol. Feb 1993;264(2 Pt 1):C361-9.
doi: 10.1152/ajpcell.1993.264.2.C361
27. Almada M, Alves P, Fonseca BM, et al. Synthetic cannabinoids JWH-018, JWH-122, UR-144 and the phytocannabinoid THC activate apoptosis in placental cells. Toxicol Lett. Feb 1 2020;319:129-137.
doi: 10.1016/j.toxlet.2019.11.004
28. Amshel CE, Fealk MH, Phillips BJ, Caruso DM. Anhydrous ammonia burns case report and review of the literature. Burns. Aug 2000;26(5):493-7.
doi: 10.1016/s0305-4179(99)00176-x
29. Zhang Y, Bhavnani BR. Glutamate-induced apoptosis in neuronal cells is mediated via caspase-dependent and independent mechanisms involving calpain and caspase-3 proteases as well as apoptosis inducing factor (AIF) and this process is inhibited by equine estrogens. BMC Neurosci. Jun 15 2006;7:49.
doi: 10.1186/1471-2202-7-49
30. Masserano JM, Baker I, Venable D, et al. Dopamine induces cell death, lipid peroxidation and DNA base damage in a catecholaminergic cell line derived from the central nervous system. Neurotox Res. Feb 2000;1(3):171-9.
doi: 10.1007/BF03033288
31. Shakhman O, Herkert M, Rose C, Humeny A, Becker CM. Induction by beta-bungarotoxin of apoptosis in cultured hippocampal neurons is mediated by Ca(2+)-dependent formation of reactive oxygen species. J Neurochem. Nov 2003;87(3):598-608.
doi: 10.1046/j.1471-4159.2003.02035.x
32. Schneider M, Marison IW, von Stockar U. The importance of ammonia in mammalian cell culture. J Biotechnol. May 15 1996;46(3):161-85.
doi: 10.1016/0168-1656(95)00196-4
33. Wang Y, Qin ZH. Molecular and cellular mechanisms of excitotoxic neuronal death. Apoptosis. Nov 2010;15(11):1382-402.
doi: 10.1007/s10495-010-0481-0
34. Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. May 25 2012;149(5):1060-72.
doi: 10.1016/j.cell.2012.03.042
35. Ziegler U, Groscurth P. Morphological features of cell death. News Physiol Sci. Jun 2004;19:124-8.
doi: 10.1152/nips.01519.2004
36. Melamed E, Offen D, Shirvan A, Djaldetti R, Barzilai A, Ziv I. Levodopa toxicity and apoptosis. Ann Neurol. Sep 1998;44(3 Suppl 1):S149-54.
doi: 10.1002/ana.410440722
37. Lister R, Pelizzola M, Kida YS, et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature. Mar 3 2011;471(7336):68-73.
doi: 10.1038/nature09798
38. Kim K, Zhao R, Doi A, et al. Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells. Nat Biotechnol. Nov 27 2011;29(12):1117-9.
doi: 10.1038/nbt.2052
39. Hawkins RD, Hon GC, Lee LK, et al. Distinct epigenomic landscapes of pluripotent and lineage-committed human cells. Cell Stem Cell. May 7 2010;6(5):479-91.
doi: 10.1016/j.stem.2010.03.018
40. Nassiri I, McCall MN. Systematic exploration of cell morphological phenotypes associated with a transcriptomic query. Nucleic Acids Res. Nov 2 2018;46(19):e116.
doi: 10.1093/nar/gky626
41. Carpenter AE, Jones TR, Lamprecht MR, et al. CellProfiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol. 2006;7(10):R100. doi: 10.1186/gb-2006-7-10-r100
42. Ziegler S, Sievers S, Waldmann H. Morphological profiling of small molecules. Cell Chem Biol. Mar 18 2021;28(3):300-319.
doi: 10.1016/j.chembiol.2021.02.012
43. Caicedo JC, Cooper S, Heigwer F, et al. Data-analysis strategies for image-based cell profiling. Nat Methods. Aug 31 2017;14(9):849-863.
doi: 10.1038/nmeth.4397
44. Reisen F, Sauty de Chalon A, Pfeifer M, Zhang X, Gabriel D, Selzer P. Linking phenotypes and modes of action through high-content screen fingerprints. Assay Drug Dev Technol. Sep 2015;13(7):415-27. doi: 10.1089/adt.2015.656
45. Ochoa JL, Bray WM, Lokey RS, Linington RG. Phenotype-Guided Natural Products Discovery Using Cytological Profiling. J Nat Prod. Sep 25 2015;78(9):2242-8. doi: 10.1021/acs.jnatprod.5b00455
46. Liberali P, Snijder B, Pelkmans L. A hierarchical map of regulatory genetic interactions in membrane trafficking. Cell. Jun 5 2014;157(6):1473-1487.
doi: 10.1016/j.cell.2014.04.029
47. Breslin S, O'Driscoll L. The relevance of using 3D cell cultures, in addition to 2D monolayer cultures, when evaluating breast cancer drug sensitivity and resistance. Oncotarget. Jul 19 2016;7(29):45745-45756.
doi: 10.18632/oncotarget.9935
48. Xu T, Fan Z, Li W, et al. Identification of two novel Chlorotoxin derivatives CA4 and CTX-23 with chemotherapeutic and anti-angiogenic potential. Sci Rep. Feb 2 2016;6:19799. doi: 10.1038/srep19799
49. Shulepko MA, Bychkov ML, Lyukmanova EN, Kirpichnikov MP. Recombinant Analogue of the Human Protein SLURP-1 Inhibits the Growth of U251 MG and A172 Glioma Cells. Dokl Biochem Biophys. Jul 2020;493(1):211-214.
doi: 10.1134/S1607672920040134
50. Lang J, Cheng Y, Rolfe A, et al. An hPSC-Derived Tissue-Resident Macrophage Model Reveals Differential Responses of Macrophages to ZIKV and DENV Infection. Stem Cell Reports. Aug 14 2018;11(2):348-362.
doi: 10.1016/j.stemcr.2018.06.006
51. Harschnitz O, Studer L. Human stem cell models to study host-virus interactions in the central nervous system. Nat Rev Immunol. Jul 2021;21(7):441-453.
doi: 10.1038/s41577-020-00474-y
52. Solari C, Vazquez Echegaray C, Cosentino MS, et al. Manganese Superoxide Dismutase Gene Expression Is Induced by Nanog and Oct4, Essential Pluripotent Stem Cells' Transcription Factors. PLoS One. 2015;10(12):e0144336.
doi: 10.1371/journal.pone.0144336
53. Miller DJ, Fort PE. Heat Shock Proteins Regulatory Role in Neurodevelopment. Front Neurosci. 2018;12:821.
doi: 10.3389/fnins.2018.00821
54. Fulda S, Gorman AM, Hori O, Samali A. Cellular stress responses: cell survival and cell death. Int J Cell Biol. 2010;2010:214074.
doi: 10.1155/2010/214074
55. Stetler RA, Gan Y, Zhang W, et al. Heat shock proteins: cellular and molecular mechanisms in the central nervous system. Prog Neurobiol. Oct 2010;92(2):184-211. doi: 10.1016/j.pneurobio.2010.05.002
56. Nicolas M, Hassan BA. Amyloid precursor protein and neural development. Development. Jul 2014;141(13):2543-8. doi: 10.1242/dev.108712
57. Liu S, Wang X, Li Y, et al. Necroptosis mediates TNF-induced toxicity of hippocampal neurons. Biomed Res Int. 2014;2014:290182.
doi: 10.1155/2014/290182
58. Nieto-Estevez V, Changarathil G, Adeyeye AO, et al. HDAC1 Regulates Neuronal Differentiation. Front Mol Neurosci. 2021;14:815808.
doi: 10.3389/fnmol.2021.815808
59. Pellizzari R, Rossetto O, Schiavo G, Montecucco C. Tetanus and botulinum neurotoxins: mechanism of action and therapeutic uses. Philos Trans R Soc Lond B Biol Sci. Feb 28 1999;354(1381):259-68. doi: 10.1098/rstb.1999.0377
doi: 10.3390/toxins2040683
2. Feldman RG. Occupational and environmental neurotoxicology. Lippincott-Raven; 1999:xix, 500 p.
3. Dubovicky M, Kovacovsky P, Ujhazy E, Navarova J, Brucknerova I, Mach M. Evaluation of developmental neurotoxicity: some important issues focused on neurobehavioral development. Interdiscip Toxicol. Dec 2008;1(3-4):206-10.
doi : 10.2478/v10102-010-0042-y
4. Plunkett LM. Developmental neurotoxicity of industrial chemicals. Lancet. Mar 10 2007;369(9564):821.
doi: 10.1016/S0140-6736(07)60396-1
5. Saunders NR, Dziegielewska KM. Developmental neurotoxicity of industrial chemicals. Lancet. Mar 10 2007;369(9564):821.
doi: 10.1016/S0140-6736(07)60397-3
6. Grandjean P, Landrigan PJ. Developmental neurotoxicity of industrial chemicals. Lancet. Dec 16 2006;368(9553):2167-78.
doi: 10.1016/S0140-6736(06)69665-7
7. Harry GJ, Billingsley M, Bruinink A, et al. In vitro techniques for the assessment of neurotoxicity. Environ Health Perspect. Feb 1998;106 Suppl 1:131-58.
doi: 10.1289/ehp.98106s1131
8. Kaur P, Aschner M, Syversen T. Biochemical factors modulating cellular neurotoxicity of methylmercury. J Toxicol. 2011;2011:721987.
doi: 10.1155/2011/721987
9. Niu N, Wang L. In vitro human cell line models to predict clinical response to anticancer drugs. Pharmacogenomics. 2015;16(3):273-85.
doi: 10.2217/pgs.14.170
10. Stoddart MJ. Cell viability assays: introduction. Methods Mol Biol. 2011;740:1-6.
doi: 10.1007/978-1-61779-108-6_1
11. Adan A, Kiraz Y, Baran Y. Cell Proliferation and Cytotoxicity Assays. Curr Pharm Biotechnol. 2016;17(14):1213-1221. doi: 10.2174/1389201017666160808160513
12. Lin L, Desai R, Wang X, Lo EH, Xing C. Characteristics of primary rat microglia isolated from mixed cultures using two different methods. J Neuroinflammation. May 8 2017;14(1):101.
doi: 10.1186/s12974-017-0877-7
13. Shin EJ, Tran HQ, Nguyen PT, et al. Role of Mitochondria in Methamphetamine-Induced Dopaminergic Neurotoxicity: Involvement in Oxidative Stress, Neuroinflammation, and Pro-apoptosis-A Review. Neurochem Res. Jan 2018;43(1):66-78.
doi: 10.1007/s11064-017-2318-5
14. Sahu MP, Nikkila O, Lagas S, Kolehmainen S, Castren E. Culturing primary neurons from rat hippocampus and cortex. Neuronal Signal. Jun 2019;3(2):NS20180207.
doi: 10.1042/NS20180207
15. Salazar IL, Mele M, Caldeira MV, et al. Preparation of Primary Cultures of Embryonic Rat Hippocampal and Cerebrocortical Neurons. Bio Protoc. Sep 20 2017;7(18):e2551.
doi: 10.21769/BioProtoc.2551
16. Luz AL, Tokar EJ. Pluripotent Stem Cells in Developmental Toxicity Testing: A Review of Methodological Advances. Toxicol Sci. Sep 1 2018;165(1):31-39.
doi: 10.1093/toxsci/kfy174
17. Romito A, Cobellis G. Pluripotent Stem Cells: Current Understanding and Future Directions. Stem Cells Int. 2016;2016:9451492.
doi:10.1155/2016/9451492
18. Tukker AM, Wijnolts FMJ, de Groot A, Westerink RHS. Human iPSC-derived neuronal models for in vitro neurotoxicity assessment. Neurotoxicology. Jul 2018; 67:215-225.
doi: 10.1016/j.neuro.2018.06.007
19. Kapalczynska M, Kolenda T, Przybyla W, et al. 2D and 3D cell cultures - a comparison of different types of cancer cell cultures. Arch Med Sci. Jun 2018;14(4):910-919.
doi: 10.5114/aoms.2016.63743
20. Park IH, Arora N, Huo H, et al. Disease-specific induced pluripotent stem cells. Cell. Sep 5 2008;134(5):877-86.
doi: 10.1016/j.cell.2008.07.041
21. Moretti A, Bellin M, Welling A, et al. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med. Oct 7 2010;363(15):1397-409.
doi: 10.1056/NEJMoa0908679
22. Ebert AD, Yu J, Rose FF, Jr., et al. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature. Jan 15 2009;457(7227):277-80.
doi: 10.1038/nature07677
23. Dasari V, Bolimera P, Krishna Gorthi L, Dravida S. In Vitro Profiling of Application Ready Human Surrogate Primary Progenitor Stromal Cell Fractions. Archives of Clinical and Biomedical Research. 2022;06(03)
doi: 10.26502/acbr.50170266
24. Huang L, Huang QY, Huang HQ. The evidence of HeLa cell apoptosis induced with tetraethylammonium using proteomics and various analytical methods. J Biol Chem. Jan 24 2014;289(4):2217-29.
doi: 10.1074/jbc.M113.515932
25. Deshane J, Garner CC, Sontheimer H. Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2. J Biol Chem. Feb 7 2003;278(6):4135-44.
doi: 10.1074/jbc.M205662200
26. DeBin JA, Maggio JE, Strichartz GR. Purification and characterization of chlorotoxin, a chloride channel ligand from the venom of the scorpion. Am J Physiol. Feb 1993;264(2 Pt 1):C361-9.
doi: 10.1152/ajpcell.1993.264.2.C361
27. Almada M, Alves P, Fonseca BM, et al. Synthetic cannabinoids JWH-018, JWH-122, UR-144 and the phytocannabinoid THC activate apoptosis in placental cells. Toxicol Lett. Feb 1 2020;319:129-137.
doi: 10.1016/j.toxlet.2019.11.004
28. Amshel CE, Fealk MH, Phillips BJ, Caruso DM. Anhydrous ammonia burns case report and review of the literature. Burns. Aug 2000;26(5):493-7.
doi: 10.1016/s0305-4179(99)00176-x
29. Zhang Y, Bhavnani BR. Glutamate-induced apoptosis in neuronal cells is mediated via caspase-dependent and independent mechanisms involving calpain and caspase-3 proteases as well as apoptosis inducing factor (AIF) and this process is inhibited by equine estrogens. BMC Neurosci. Jun 15 2006;7:49.
doi: 10.1186/1471-2202-7-49
30. Masserano JM, Baker I, Venable D, et al. Dopamine induces cell death, lipid peroxidation and DNA base damage in a catecholaminergic cell line derived from the central nervous system. Neurotox Res. Feb 2000;1(3):171-9.
doi: 10.1007/BF03033288
31. Shakhman O, Herkert M, Rose C, Humeny A, Becker CM. Induction by beta-bungarotoxin of apoptosis in cultured hippocampal neurons is mediated by Ca(2+)-dependent formation of reactive oxygen species. J Neurochem. Nov 2003;87(3):598-608.
doi: 10.1046/j.1471-4159.2003.02035.x
32. Schneider M, Marison IW, von Stockar U. The importance of ammonia in mammalian cell culture. J Biotechnol. May 15 1996;46(3):161-85.
doi: 10.1016/0168-1656(95)00196-4
33. Wang Y, Qin ZH. Molecular and cellular mechanisms of excitotoxic neuronal death. Apoptosis. Nov 2010;15(11):1382-402.
doi: 10.1007/s10495-010-0481-0
34. Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. May 25 2012;149(5):1060-72.
doi: 10.1016/j.cell.2012.03.042
35. Ziegler U, Groscurth P. Morphological features of cell death. News Physiol Sci. Jun 2004;19:124-8.
doi: 10.1152/nips.01519.2004
36. Melamed E, Offen D, Shirvan A, Djaldetti R, Barzilai A, Ziv I. Levodopa toxicity and apoptosis. Ann Neurol. Sep 1998;44(3 Suppl 1):S149-54.
doi: 10.1002/ana.410440722
37. Lister R, Pelizzola M, Kida YS, et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature. Mar 3 2011;471(7336):68-73.
doi: 10.1038/nature09798
38. Kim K, Zhao R, Doi A, et al. Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells. Nat Biotechnol. Nov 27 2011;29(12):1117-9.
doi: 10.1038/nbt.2052
39. Hawkins RD, Hon GC, Lee LK, et al. Distinct epigenomic landscapes of pluripotent and lineage-committed human cells. Cell Stem Cell. May 7 2010;6(5):479-91.
doi: 10.1016/j.stem.2010.03.018
40. Nassiri I, McCall MN. Systematic exploration of cell morphological phenotypes associated with a transcriptomic query. Nucleic Acids Res. Nov 2 2018;46(19):e116.
doi: 10.1093/nar/gky626
41. Carpenter AE, Jones TR, Lamprecht MR, et al. CellProfiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol. 2006;7(10):R100. doi: 10.1186/gb-2006-7-10-r100
42. Ziegler S, Sievers S, Waldmann H. Morphological profiling of small molecules. Cell Chem Biol. Mar 18 2021;28(3):300-319.
doi: 10.1016/j.chembiol.2021.02.012
43. Caicedo JC, Cooper S, Heigwer F, et al. Data-analysis strategies for image-based cell profiling. Nat Methods. Aug 31 2017;14(9):849-863.
doi: 10.1038/nmeth.4397
44. Reisen F, Sauty de Chalon A, Pfeifer M, Zhang X, Gabriel D, Selzer P. Linking phenotypes and modes of action through high-content screen fingerprints. Assay Drug Dev Technol. Sep 2015;13(7):415-27. doi: 10.1089/adt.2015.656
45. Ochoa JL, Bray WM, Lokey RS, Linington RG. Phenotype-Guided Natural Products Discovery Using Cytological Profiling. J Nat Prod. Sep 25 2015;78(9):2242-8. doi: 10.1021/acs.jnatprod.5b00455
46. Liberali P, Snijder B, Pelkmans L. A hierarchical map of regulatory genetic interactions in membrane trafficking. Cell. Jun 5 2014;157(6):1473-1487.
doi: 10.1016/j.cell.2014.04.029
47. Breslin S, O'Driscoll L. The relevance of using 3D cell cultures, in addition to 2D monolayer cultures, when evaluating breast cancer drug sensitivity and resistance. Oncotarget. Jul 19 2016;7(29):45745-45756.
doi: 10.18632/oncotarget.9935
48. Xu T, Fan Z, Li W, et al. Identification of two novel Chlorotoxin derivatives CA4 and CTX-23 with chemotherapeutic and anti-angiogenic potential. Sci Rep. Feb 2 2016;6:19799. doi: 10.1038/srep19799
49. Shulepko MA, Bychkov ML, Lyukmanova EN, Kirpichnikov MP. Recombinant Analogue of the Human Protein SLURP-1 Inhibits the Growth of U251 MG and A172 Glioma Cells. Dokl Biochem Biophys. Jul 2020;493(1):211-214.
doi: 10.1134/S1607672920040134
50. Lang J, Cheng Y, Rolfe A, et al. An hPSC-Derived Tissue-Resident Macrophage Model Reveals Differential Responses of Macrophages to ZIKV and DENV Infection. Stem Cell Reports. Aug 14 2018;11(2):348-362.
doi: 10.1016/j.stemcr.2018.06.006
51. Harschnitz O, Studer L. Human stem cell models to study host-virus interactions in the central nervous system. Nat Rev Immunol. Jul 2021;21(7):441-453.
doi: 10.1038/s41577-020-00474-y
52. Solari C, Vazquez Echegaray C, Cosentino MS, et al. Manganese Superoxide Dismutase Gene Expression Is Induced by Nanog and Oct4, Essential Pluripotent Stem Cells' Transcription Factors. PLoS One. 2015;10(12):e0144336.
doi: 10.1371/journal.pone.0144336
53. Miller DJ, Fort PE. Heat Shock Proteins Regulatory Role in Neurodevelopment. Front Neurosci. 2018;12:821.
doi: 10.3389/fnins.2018.00821
54. Fulda S, Gorman AM, Hori O, Samali A. Cellular stress responses: cell survival and cell death. Int J Cell Biol. 2010;2010:214074.
doi: 10.1155/2010/214074
55. Stetler RA, Gan Y, Zhang W, et al. Heat shock proteins: cellular and molecular mechanisms in the central nervous system. Prog Neurobiol. Oct 2010;92(2):184-211. doi: 10.1016/j.pneurobio.2010.05.002
56. Nicolas M, Hassan BA. Amyloid precursor protein and neural development. Development. Jul 2014;141(13):2543-8. doi: 10.1242/dev.108712
57. Liu S, Wang X, Li Y, et al. Necroptosis mediates TNF-induced toxicity of hippocampal neurons. Biomed Res Int. 2014;2014:290182.
doi: 10.1155/2014/290182
58. Nieto-Estevez V, Changarathil G, Adeyeye AO, et al. HDAC1 Regulates Neuronal Differentiation. Front Mol Neurosci. 2021;14:815808.
doi: 10.3389/fnmol.2021.815808
59. Pellizzari R, Rossetto O, Schiavo G, Montecucco C. Tetanus and botulinum neurotoxins: mechanism of action and therapeutic uses. Philos Trans R Soc Lond B Biol Sci. Feb 28 1999;354(1381):259-68. doi: 10.1098/rstb.1999.0377