Exploring mood disorders and treatment options using human stem cells

Hudock, Autumn; Leal, Zaira Paulina; Sharma, Amandeep; Mei, Arianna; Santos, Renata; Marchetto, Maria Carolina

doi:10.1590/1678-4685-GMB-2023-0305

Autumn Hudock

conceptualized the manuscript

supervised the other authors

performed literature research

curated the bibliography

wrote the manuscript

designed and generated figures and tables

reviewed and edited the manuscript

approved the final version of the manuscript

University of California San Diego, Department of Anthropology, La Jolla, CA, USA.

https://orcid.org/0000-0002-4722-754X

Zaira Paulina Leal

performed literature research

curated the bibliography

wrote the manuscript

designed and generated figures and tables

reviewed and edited the manuscript

approved the final version of the manuscript

University of California San Diego, Department of Anthropology, La Jolla, CA, USA.

https://orcid.org/0009-0002-2902-9248

Amandeep Sharma

designed and generated figures and tables

analyzed the data

wrote the methodology session

reviewed and edited the manuscript

approved the final version of the manuscript

The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, CA, USA.

https://orcid.org/0000-0002-2091-9618

Arianna Mei

conducted the experiments

analyzed the data

reviewed and edited the manuscript

approved the final version of the manuscript

The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, CA, USA.

Renata Santos

conducted the experiments

reviewed and edited the manuscript

approved the final version of the manuscript

The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, CA, USA.

Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Signaling Mechanisms in Neurological Disorders, Paris, France.

Institut des Sciences Biologiques, Centre National de la Recherche Scientifique (CNRS), Paris, France.

https://orcid.org/0000-0002-3085-5128

Maria Carolina Marchetto

conceptualized the manuscript

supervised the other authors

approved the final version of the manuscript

University of California San Diego, Department of Anthropology, La Jolla, CA, USA.

https://orcid.org/0000-0002-0449-9051

Send correspondence to Maria Carolina Marchetto. University of California San Diego, Department of Anthropology, 9500 Gilman Drive, MC 0532, La Jolla, CA, USA. E-mail: mcmarchetto@ucsd.edu.

Associate Editor:

Alberto R. Kornblihtt

Conflict of Interest

The authors declare that there is no conflict of interest that could be perceived as prejudicial to the impartiality of the reported research.

Figures (3)
Tables (2)

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Figure 1 -
Using patient-iPSC models to study mood disorders. Patient skin or blood cells are collected and reprogrammed into iPSC using previously established protocols (see methods). The iPSCs are then differentiated into neuronal or glial progenitor cells in 2 or 3D cultures and matured into functional neurons and glial cells. These cells can then be used to study the disease pathophysiology, response to inflammatory stimuli and drug screening for novel therapeutic compounds. The graph represents the protocol of establishing cell lines in tissue culture settings to study mood disorders affecting the brain, beginning with the recruitment of cells, the process of reprogramming cells into iPSCs, and differentiating them into various neuronal cell types.

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Figure 2 -
Apigenin attenuated the inflammation response more effectively in iPSCs-derived astrocytes from BD patients. (A) Schematics of investigating anti-inflammatory attributes of a flavonoid (Apigenin). iPSC, glial progenitor cells (GPCs) and astrocytes derived from three neurotypical and six BD donors, described previously (Santos et al., 2017Santos R, Vadodaria KC, Jaeger BN, Mei A, Lefcochilos-Fogelquist S, Mendes APD, Erikson G, Shokhirev M, Randolph-Moore L, Fredlender C et al. (2017) Differentiation of inflammation-responsive astrocytes from glial progenitors generated from human induced pluripotent stem cells. Stem Cell Reports 8:1757-1769.; Vadodaria et al., 2021Vadodaria KC, Mendes APD, Mei A, Racha V, Erikson G, Shokhirev MN, Oefner R, Heard KJ, McCarthy MJ, Eyler L et al. (2021) Altered neuronal support and inflammatory response in bipolar disorder patient-derived astrocytes. Stem Cell Reports 16:825-835.) were used in this study. This assay was previously described by Vadodaria et al. (2021). Briefly, pro-inflammatory stimuli were added to 4-week-old astrocytes for 5 hours, either by using recombinant human IL-1b (10 ng/mL) or recombinant human TNF-a (50 ng/mL); PBS was used as a non-stimulated control. To mitigate the inflammatory response, astrocytes were simultaneously treated with 20 μM Apigenin. BD GolgiPlug and BD GolgiStop were added to the treatments to inhibit extracellular protein secretion. Flow cytometry was used to quantify IL-6 producing cells. Astrocytes were dissociated using a 1:1 ratio of accutase/papain followed by staining with Zombie UV fixable Viability kit. The BD Cytofix/Cytoperm and BD Perm/Wash kits were used for fixing and permeabilizing the cells. Subsequently, IL-6 cytokine was labeled with APC conjugated anti-IL-6 antibody in BD Perm/Wash for 20 min. Data collection and analysis were conducted using a BD CantoII cytometer and FlowJo software, respectively. Negative gating controls for anti-IL-6 were done in non-stimulated samples stained with rat IgG1-APC antibody. The IL-6 positive cells were quantified by normalizing the data with non-stimulated cells from the vehicle treated cells. Data are from two biological experiments with technical replicates (3). (B & C) Bar graph representing the quantification of astrocytes expressing IL-6 cytokine post 5 hours of exposure to Vehicle or IL1-b or IL1-b+Apigenin (B) or Vehicle or TNF-a or TNF-a+Apigenin (C), mean ± SEM. Two-way Anova test was used to determine the statistical significance.

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Figure 3 -
Exploring alternative treatment methods for BD and MDD non-responders to lithium and SSRIs/ SNRIs using iPSC models. The graph depicts the pathways that researchers have used to explore alternative treatment methods beyond lithium and SSRIs/SNRIs for non-responders with BD and MDD, as they make up about half of the population for those diagnosed with both disorders (Tighe et al., 2011Tighe SK, Mahon PB and Potash JB (2011) Predictors of lithium response in bipolar disorder. Ther Adv Chronic Dis 2:209-226.; Taliaz et al., 2021Taliaz D, Spinrad A, Barzilay R, Barnett-Itzhaki Z, Averbuch D, Teltsh O, Schurr R, Darki-Morag S and Lerer B (2021) Optimizing prediction of response to antidepressant medications using machine learning and integrated genetic, clinical, and demographic data. Transl Psychiatry 11:e381.). Beginning with the collection of cells, researchers can look for biomarkers associated with drug responsiveness, and model personalized neuronal models of patients that can be subjected to various forms of analysis. This data can contribute to the exploration of new compounds and alternative drugs already on the market, leading to relief for non-responders of traditional treatment methods.

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Table 1 -
Induced pluripotent stem cells in the study of bipolar disorder: a chronological table of exploratory and treatment-based studies.

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Table 2 -
Induced pluripotent stem cells in the study of major depressive disorder: a chronological table of exploratory and treatment based studies.

Figure 2 - Apigenin attenuated the inflammation response more effectively in iPSCs-derived astrocytes from BD patients. (A) Schematics of investigating anti-inflammatory attributes of a flavonoid (Apigenin). iPSC, glial progenitor cells (GPCs) and astrocytes derived from three neurotypical and six BD donors, described previously (Santos et al., 2017Santos R, Vadodaria KC, Jaeger BN, Mei A, Lefcochilos-Fogelquist S, Mendes APD, Erikson G, Shokhirev M, Randolph-Moore L, Fredlender C et al. (2017) Differentiation of inflammation-responsive astrocytes from glial progenitors generated from human induced pluripotent stem cells. Stem Cell Reports 8:1757-1769.; Vadodaria et al., 2021Vadodaria KC, Mendes APD, Mei A, Racha V, Erikson G, Shokhirev MN, Oefner R, Heard KJ, McCarthy MJ, Eyler L et al. (2021) Altered neuronal support and inflammatory response in bipolar disorder patient-derived astrocytes. Stem Cell Reports 16:825-835.) were used in this study. This assay was previously described by Vadodaria et al. (2021). Briefly, pro-inflammatory stimuli were added to 4-week-old astrocytes for 5 hours, either by using recombinant human IL-1b (10 ng/mL) or recombinant human TNF-a (50 ng/mL); PBS was used as a non-stimulated control. To mitigate the inflammatory response, astrocytes were simultaneously treated with 20 μM Apigenin. BD GolgiPlug and BD GolgiStop were added to the treatments to inhibit extracellular protein secretion. Flow cytometry was used to quantify IL-6 producing cells. Astrocytes were dissociated using a 1:1 ratio of accutase/papain followed by staining with Zombie UV fixable Viability kit. The BD Cytofix/Cytoperm and BD Perm/Wash kits were used for fixing and permeabilizing the cells. Subsequently, IL-6 cytokine was labeled with APC conjugated anti-IL-6 antibody in BD Perm/Wash for 20 min. Data collection and analysis were conducted using a BD CantoII cytometer and FlowJo software, respectively. Negative gating controls for anti-IL-6 were done in non-stimulated samples stained with rat IgG1-APC antibody. The IL-6 positive cells were quantified by normalizing the data with non-stimulated cells from the vehicle treated cells. Data are from two biological experiments with technical replicates (3). (B & C) Bar graph representing the quantification of astrocytes expressing IL-6 cytokine post 5 hours of exposure to Vehicle or IL1-b or IL1-b+Apigenin (B) or Vehicle or TNF-a or TNF-a+Apigenin (C), mean ± SEM. Two-way Anova test was used to determine the statistical significance.

Study Type	Treatment	Cell/ Tissue Type(s)	iPSCs Relevance	Findings	Reference
Exploratory	N/a	iPSCs Neurons	Investigation of the cellular behavior and developmental pathways of iPSC derived neurons from BD patients and controls	-Increased membrane receptors and ion-controlled genes were noted in BD patient derived neurons compared to controls	Chen et al. (2014Chen HM, DeLong CJ, Bame M, Rajapakse I, Herron TJ, McInnis MG and O’Shea KS (2014) Transcripts involved in calcium signaling and telencephalic neuronal fate are altered in induced pluripotent stem cells from bipolar disorder patients. Transl Psychiatry 4:e375.)
Exploratory	N/a	Postmortem cerebral tissue iPSCs Neurons NPCs	Examination of the expression of hsa-miR-34a in postmortem tissue and various IPSCs derived cell types	-Increased expression of microRNAs in BD patient derived iPSC cultures and postmortem cerebral tissue	Bavamian et al. (2015Bavamian S, Mellios N, Lalonde J, Fass DM, Wang J, Sheridan SD, Madison JM, Zhou F, Rueckert EH, Barker D et al. (2015) Dysregulation of miR-34a links neuronal development to genetic risk factors for bipolar disorder. Mol Psychiatry 20:573-584.)
Exploratory	N/a	iPSCs NPCs Neurons	Models of iPSCs, NPCs and neurons of a 1^st degree family cohort analyzed using microarray technology to investigate the existence of global gene expression patterns in individuals with BD	-Differently expressed genes were observed during iPSC to NPC differentiation in BD patients -Enrichment of genes correlated with cell cycle regulation and homeostasis	Kim et al. (2015Kim KH, Liu J, Sells Galvin RJ, Dage JL, Egeland JA, Smith RC, Merchant KM and Paul SM (2015) Transcriptomic analysis of induced pluripotent stem cells derived from patients with bipolar disorder from an old order amish pedigree. PLoS One 10:e0142693.)
Exploratory	N/a	iPSCs Neurons NPCs	A family-based paradigm model was used to examine iPSCs lines from brothers with DB compared to non-BD parents	-NPCs and neuronal cells derived from BD patients showed phenotypical differences in channeled subunits and Wnt pathway components related to neuroplasticity	Madison et al. (2015Madison JM, Zhou F, Nigam A, Hussain A, Barker DD, Nehme R, van der Ven K, Hsu J, Wolf P, Fleishman M et al. (2015) Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities. Mol Psychiatry 20:703-717.)
Exploratory and Treatment	Lithium	iPSC-derived neurons	Study of phenotypical differences in neurons derived from iPSCs generated from lithium responder and non-responder patients and controls	- Discovered that BD derived neurons were hyperexcitable compared to control neurons -Lithium reversed hyperexcitability only on neurons derived from lithium responders	Mertens et al. (2015Mertens J, Wang Q-W, Kim Y, Yu DX, Pham S, Yang B, Zheng Y, Diffenderfer KE, Zhang J, Soltani S et al. (2015) Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nat 527:95-99., 2016)
Treatment	Lithium	iPSC-derived neurons	Study of neurons derived from BD lithium responder patients to gain insight to BD molecular mechanisms and lithium targets	-Lithium acts on CRMP2 which alters neuronal cytoskeletal dynamics and spine formation in BD iPSC derived neurons	Tobe et al. (2017Tobe BTD, Crain AM, Winquist AM, Calabrese B, Makihara H, Zhao W, Lalonde J, Nakamura H, Konopaske G, Sidor M et al. (2017) Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis. Proc Natl Acad Sci U S A 114:e4462-e4471.)
Exploratory	N/a	iPSCs NPCs	Examination of transcriptomes during the transition from iPSCs to NPCs in BD patients and controls using RNA sequencing	-Increased expression of genes related to inflammation in BD-derived NPCs -The most significantly differentially expressed genes were NLRP2 and genes associated with GABA and dopamine receptor canonical pathways	Vizlin-Hodzic et al. (2017Vizlin-Hodzic D, Zhai Q, Illes S, Södersten K, Truvé K, Parris TZ, Sobhan PK, Salmela S, Kosalai ST, Kanduri C et al. (2017) Early onset of inflammation during ontogeny of bipolar disorder: The NLRP2 inflammasome gene distinctly differentiates between patients and healthy controls in the transition between iPS cell and neural stem cell stages. Transl Psychiatry 7:e1010.)
Exploratory	N/a	iPSC-derived neurons	Modeled and compared activity of neurons derived iPSCs from lithium responders and non-responders BD patients	-Created a model to predict if a patient will respond to lithium or not with a 92% accuracy rate	Stern et al. (2018Stern S, Santos R, Marchetto MC, Mendes APD, Rouleau GA, Biesmans S, Wang Q-W, Yao J, Charnay P, Bang AG et al. (2018) Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients’ responsiveness to lithium. Mol Psychiatry 23:1453-1465.)
Exploratory	N/a	iPSC-derived neurons	Study of the behavior of neurons of hippocampus CA3 and dentate gyrus and motor neurons from lithium responders and non-responders BD patients	- Hyperexcitability is dependent on the type of neurons and unstable in neurons derived from lithium non-responders	Stern et al. (2020aStern S, Sarkar A, Galor D, Stern T, Mei A, Stern Y, Mendes APD, Randolph-Moore L, Rouleau G, Bang AG et al. (2020a) A physiological instability displayed in hippocampal neurons derived from lithium-nonresponsive bipolar disorder patients. Biol Psychiatry 88:150-158.,bStern S, Sarkar A, Stern T, Mei A, Mendes APD, Stern Y, Goldberg G, Galor D, Nguyen T, Randolph-Moore L et al. (2020b) Mechanisms underlying the hyperexcitability of CA3 and dentate gyrus hippocampal neurons derived from patients with bipolar disorder. Biol Psychiatry 88:139-149.)
Exploratory	N/a	Organoids	Exploration of functional mechanisms in BD by comparing BD-derived and control organoids	-BD derived patient neurons expressed upregulation of genes involved in neurogenesis, cell adhesion, synaptic morphology, and function and a downregulation of genes involved in immune signaling along with a reduction in mitochondria-associated endoplasmic reticulum membranes (MAMs) -BD derived organoids responded differently to electrical stimuli but similarly to non-BD derived models in the absence of electrical stimuli	Kathuria et al. (2020Kathuria A, Lopez-Lengowski K, Vater M, McPhie D, Cohen BM and Karmacharya R (2020) Transcriptome analysis and functional characterization of cerebral organoids in bipolar disorder. Genome Med 12:e34.)
Treatment	Lithium	iPSC-derived NPCs and lymphoblastoid cell lines	Examination of cellular phenotypes of lithium responder and non-responder BD patients compared to healthy controls	-In vitro lithium treatment of BD derived iPSC lines encouraged cell proliferation, enhanced the expression of BCL2 and GSK3B and lowered mitochondrial membrane potential (MMP) - Low MMP was reversed using in vitro lithium exposure but remained unaffected in clinical lithium therapy treatment	Paul et al. (2020Paul P, Iyer S, Nadella RK, Nayak R, Chellappa AS, Ambardar S, Sud R, Sukumaran SK, Purushottam M, Jain S et al. (2020) Lithium response in bipolar disorder correlates with improved cell viability of patient derived cell lines. Sci Rep 10:e7428.)
Treatment	Valproate	iPSCs	Examination of how valproate interacts with iPSCs from lithium responders and non-responders	-Valproate rescued dysregulation of cell proliferation and cell death in lithium responders and non-responders	Paul et al. (2020Paul P, Iyer S, Nadella RK, Nayak R, Chellappa AS, Ambardar S, Sud R, Sukumaran SK, Purushottam M, Jain S et al. (2020) Lithium response in bipolar disorder correlates with improved cell viability of patient derived cell lines. Sci Rep 10:e7428.)
Exploratory	N/a	iPSC-derived astrocytes	Generated astrocyte models derived from iPSC from BD patients and controls to examine inflammation related phenotypes	-IL-6, a proinflammatory cytokine, was upregulated in iPSC-derived astrocytes from BD patients compared to controls -When BD iPSC derived astrocytes were co-cultured with neurons, there was a reduction in neuronal activity	Vadodaria et al. (2021Vadodaria KC, Mendes APD, Mei A, Racha V, Erikson G, Shokhirev MN, Oefner R, Heard KJ, McCarthy MJ, Eyler L et al. (2021) Altered neuronal support and inflammatory response in bipolar disorder patient-derived astrocytes. Stem Cell Reports 16:825-835.)
Exploratory and Treatment	Lithiumand Valproic Acid	iPSC-derived neurons	Examined lithium resistance in iPSC-derived neurons derived from lithium non-responder patients with B	-NR neurons displayed less activity of the Wnt/β-catenin signaling pathway and a significant decrease in LEF1 expression	Santos et al. (2021Santos R, Linker SB, Stern S, Mendes APD, Shokhirev MN, Erikson G, Randolph-Moore L, Racha V, Kim Y, Kelsoe JR et al. (2021) Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients. Mol Psychiatry 26:2440-2456.)
Exploratory	N/a	Stem Cells Neurons NPCs	Mapped the presence and arrangement of lithium ions in cells	-Unveiled the mechanisms of lithium ion distribution in multiple cell types including patient derived cells from individuals with BD to further explore and understand lithium- response pathways	McGhee et al. (2021McGhee CE, Yang Z, Guo W, Wu Y, Lyu M, DeLong CJ, Hong S, Ma Y, McInnis MG, O’Shea KS et al. (2021) DNAzyme-based lithium-selective imaging reveals higher lithium accumulation in bipolar disorder patient-derived neurons. ACS Cent Sci 7:1809-1820.)
Exploratory	N/a	iPSC-derived neurons	Examined the circadian-rhythm regulation in neurons derived from iPSCs of BD lithium responder and non-responder patients	- BD neurons showed differences in circadian-rhythm regulation with the most significant difference seen in lithium non-responders	Mishra et al. (2021Mishra HK, Ying NM, Luis A, Wei H, Nguyen M, Nakhla T, Vandenburgh S, Alda M, Berrettini WH, Brennand KJ et al. (2021) Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: Preliminary studies. Mol Psychiatry 26:3383-3394.)
Treatment	Trimetazidine	iPSC-derived neurons and astrocytes	Study aimed to repurpose trimetazidine to treat bipolar depression	- Trimetazidine increased the production of ATP, which can be deficient in BD patients, by altering cellular metabolic processes	Bortolasci et al. (2023Bortolasci CC, Kidnapillai S, Spolding B, Truong TTT, Connor T, Swinton C, Panizzutti B, Liu ZSJ, Sanigorski A, Dean OM et al. (2023) Use of a gene expression signature to identify trimetazidine for repurposing to treat bipolar depression. Bipolar Disord 25:661-670.)
Treatment	Lithium	iPSC-derived cortical spheroids	Examination of phenotypic effects of prolonged lithium exposure on corticoid spheroids derived from BD patients	-BD patient-derived corticoid spheroids exhibited transcriptional profiles with enriched differentially expressed genes associated with kidney function and ion homeostasis when exposed to chronic lithium treatment	Osete et al. (2023Osete JR, Akkouh IA, Ievglevskyi O, Vandenberghe M, de Assis DR, Ueland T, Kondratskaya E, Holen B, Szabo A, Hughes T et al. (2023) Transcriptional and functional effects of lithium in bipolar disorder iPSC-derived cortical spheroids. Mol Psychiatry 28:3033-3043.)
Treatment	Apigenin	iPSC-derived astrocytes	Tested the effects of apigenin, a neuroprotective and anti-inflammatory compound, on stimulated iPSC-derived astrocytes from BD and control individuals to examine alternative treatment methods for bipolar disorder	-BD and control astrocytes experienced an increase in the percentage of IL-6 expressing astrocytes irrespective of the proinflammatory stimuli used (IL-1b or TNF-a) - Both BD and control astrocytes showed higher sensitivity to proinflammatory cytokine IL-6 compared to TNF-a -Apigenin treatment successfully counteracted the inflammatory response in BD and control astrocytes	This study

Study Type	Treatment	Cell/ Tissue Type(s)	Involvement of iPSCs in Study	Findings	Reference
Exploratory and Treatment	Sertraline	HPCs	Exploratory: To examine the effects of chronic stress, a known cofounder of depression, researchers exposed HPCs from healthy individuals to cortisol and dexamethasone (or dex, synthetic cortisol) Treatment: The HPCs were then treated with sertraline, the most prescribed SSRI for MDD	Exploratory: -Healthy HPCs exposed to dex and cortisol exhibited a decrease in cell proliferation and neuronal differentiation -Increased expression of genes involved in cell cycle inhibition Treatment: -Increase in glucocorticoid receptor transcription rate -Alterations in neurogenesis associated gene expression profiles	Anacker et al. (2011Anacker C, Zunszain PA, Cattaneo A, Carvalho LA, Garabedian MJ, Thuret S, Price J and Pariante CM (2011) Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor. Mol Psychiatry 16:738-750.)
Exploratory	N/a	HPCs	This study explored the effects of proinflammatory cytokine interleukin-1b (IL-1b) on neuronal generation	-Increase in transcripts for kynurenine 3-monooxygenase (KMO) enzyme during cell differentiation -Blocking KMO resulted in the restoration reduced neurogenesis caused by IL-1b exposure	Zunszain et al. (2012Zunszain PA, Anacker C, Cattaneo A , Choudhury S, Musaelyan K, Myint AM, Thuret S , Price J and Pariante CM (2012) Interleukin-1β: A new regulator of the kynurenine pathway affecting human hippocampal neurogenesis. Neuropsychopharmacol 37:939-949.)
Exploratory	N/a	HPCs	Examined the effects of cortisol exposure in MDD vs non-MDD hippocampal progenitor cells	-Increase in cell proliferation -Decrease in neurogenesis	Anacker et al. (2013aAnacker C, Cattaneo A, Luoni A, Musaelyan K, Zunszain PA, Milanesi E, Rybka J, Berry A, Cirulli F, Thuret S et al. (2013a) Glucocorticoid-related molecular signaling pathways regulating hippocampal neurogenesis. Neuropsychopharmacol 38:872-883.)
Treatment	Glucocorticoid regulated kinase 1 (SKG1)	HPCs	Explored the effects of glucocorticoid regulated kinase 1 (SKG1) on HPCs following cortisol exposure	-The effects of cortisol exposure in HPCs can be mitigated by SKG1	Anacker et al. (2013bAnacker C, Cattaneo A, Musaelyan K, Zunszain PA, Horowitz M, Molteni R, Luoni A, Calabrese F, Tansey K, Gennarelli M et al. (2013b) Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis. Proc Natl Acad Sci U S A110:8708-8713.)
Treatment	Sertraline	hAD-SCs	Examined the changes in human adipose-derived stem cells after sertraline treatment	-Increase in proliferation	Razavi et al. (2014Razavi S, Jahromi M, Amirpour N and Khosravizadeh Z (2014) Effect of sertraline on proliferation and neurogenic differentiation of human adipose-derived stem cells. Adv Biomed Res 3:e97.)
Treatment	Venlafaxine (SNRI) Eicosapentaenoic acid (EPA) Sertraline (SSRI) docosahexaenoic acid (DHA)	HPCs	HPCs were treated with IL-1b to induce inflammation followed by exposure of various forms of treatment for MDD to examine the difference in molecular mechanisms by treatment	-Venlafaxine and eicosapentaenoic acid had anti-inflammatory effects HPCs exposed to IL-1b -Sertraline and docosahexaenoic acid had pro-inflammatory effects on IL-1b treated HPCs -All treatments were associated with a decrease in NF-kB pathway activity	Horowitz et al. (2015Horowitz MA, Wertz J, Zhu D, Cattaneo A , Musaelyan K, Nikkheslat N, Thuret S , Pariante CM and Zunszain PA (2015) Antidepressant compounds can be both pro- and anti-inflammatory in human hippocampal cells. Int J Neuropsychopharmacol 18:pyu076.)
Treatment	Paroxetine	Neurons	Explored the effects of paroxetine neuronal differentiation and cell proliferation on adipose-derived stem cells	-Paroxetine enhanced neurogenic differentiation and proliferation rate	Jahromi et al. (2016Jahromi M, Razavi S, Amirpour N and Khosravizadeh Z (2016) Paroxetine can enhance neurogenesis during neurogenic differentiation of human adipose-derived stem cells. Avicenna J Med Biotechnol 8:152-158.)
Treatment	IL-1b	HPCs	Treated HPCs with IL-1b to examine effects on the kynurenic pathway	-IL-1b exposure lead to a restoration of neurogenesis	Borsini et al. (2017Borsini A, Alboni S, Horowitz MA, Tojo LM, Cannazza G, Su K-P, Pariante CM and Zunszain PA (2017) Rescue of IL-1β-induced reduction of human neurogenesis by omega-3 fatty acids and antidepressants. Brain Behav Immun 65:230-238.)
Exploratory	N/a	HPCs	The effects of interferon-a to investigate the mechanisms of inflammation-induced depression	-Reduction in neurogenesis -Increased cell death -Increase in expression of ubiquitin-specific peptidase 18 (USP18) and interferon-stimulated gene 15 (ISG15) was responsible for the reduction of neurogenesis -Increased expression in interleukin-6 (IL-6) is responsible for the increase in cell death	Borsini et al. (2018Borsini A, Cattaneo A, Malpighi C, Thuret S, Harrison NA, MRC ImmunoPsychiatry Consortium, Zunszain PA and Pariante CM (2018) Interferon-alpha reduces human hippocampal neurogenesis and increases apoptosis via activation of distinct STAT1-dependent mechanisms. Int J Neuropsychopharmacol 21:187-200.)
Treatment	Ketamine	Neurons	Examined the effects of ketamine on prefrontal hippocampal neurons derived from MDD patients	-Ketamine increased structural plasticity in MDD derived dopaminergic neurons	Cavalleri et al. (2018Cavalleri L, Merlo Pich E, Millan MJ, Chiamulera C, Kunath T, Spano PF and Collo G (2018) Ketamine enhances structural plasticity in mouse mesencephalic and human iPSC-derived dopaminergic neurons via AMPAR-driven BDNF and mTOR signaling. Mol Psychiatry 23:812-823.)
Exploratory	Ketamine	Neurons	Examined current literature on ketamine exposure on iPSCs to treat MDD	-Glutamate burst induced structural plasticity	Collo and Merlo Pitch (2018Collo G and Merlo Pich E (2018) Ketamine enhances structural plasticity in human dopaminergic neurons: Possible relevance for treatment-resistant depression. Neural Regen Res 13:645-646.)
Exploratory	N/a	HPCs	Exposure of serum derived from patients with MDD on HPCs from non-MDD study participants	-Treated HPCs showed an increase in cell apoptosis and a decrease in neurogenesis matching that of MDD patient derived HPCs -Increase in apoptosis and decrease in neurogenesis exacerbated following interferon-a treatment	Borsini et al. (2019Borsini A , Pariante CM, Zunszain PA, Hepgul N, Russell A, Zajkowska Z, Mondelli V and Thuret S (2019) The role of circulatory systemic environment in predicting interferon-alpha-induced depression: The neurogenic process as a potential mechanism. Brain Behav Immun 81:220-227.)
Treatment	Ropinirole and Pramipexole	Neurons	Examined the effect of ropinirole and pramipexole on neurons derived from patients with treatment resistant depression	-Ropinirole and pramipexole regulated structural plasticity in neurons derived from treatment resistant depression patients	Collo et al. (2018bCollo G, Cavalleri L, Chiamulera C and Merlo Pich E (2018b) (2R,6R)-Hydroxynorketamine promotes dendrite outgrowth in human inducible pluripotent stem cell-derived neurons through AMPA receptor with timing and exposure compatible with ketamine infusion pharmacokinetics in humans. NeuroReport 29:1425-1430.)
Treatment	Serotonin and Latuda	Neurons	Treatment (Serotonin): Exposed neurons derived from non-SSRI responders to Serotonin to examine changes in activity Treatment (Latuda): Exposed SSRI non-responders to Latuda, an antipsychotic drug) to examine changes in activity	-Serotonin: Increase in activity related to the upregulation of excitatory serotonergic receptors (5-HT7 and 5-HT2A), -Latuda rescued hyperactivity in SSRI non responders	Vadodaria et al. (2019aVadodaria KC, Ji Y, Skime M, Paquola A, Nelson T, Hall-Flavin D, Fredlender C, Heard KJ, Deng Y, Le AT et al. (2019a) Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons. Mol Psychiatry 24:795-807.)
Exploratory and Treatment		iPSC-derived serotonergic neurons	Exploratory: iPSCs from SSRI responders, non-responders and individuals with no history of MDD were juxtaposed to study differences in morphology, action and behavior Treatment: Treated cells with SSRIs to study the differences in the expression of serotonergic genes between the controlled and patient groups	-Exploratory: No difference found in the expression of serotonergic genes -Treatment: In SSRI non-responders, the genes protocadherin alpha 6 and alpha 8 exhibited were differentially expressed compared to SSRI responders	Vadodaria et al. (2019bVadodaria KC, Ji Y, Skime M, Paquola AC, Nelson T, Hall-Flavin D, Heard KJ, Fredlender C, Deng Y, Elkins J et al. (2019b) Altered serotonergic circuitry in SSRI-resistant major depressive disorder patient-derived neurons. Mol Psychiatry 24:808-818.)
Exploratory	N/a	HPCs	Examined the effects of IL-6 on HPCs from MDD and non-MDD derived HPCs	-Pro and anti-inflammatory effects on HPCs based on levels and presence of other cytokines	Borsini et al. (2020Borsini A , Di Benedetto MG, Giacobbe J and Pariante CM (2020) Pro- and anti-inflammatory properties of interleukin in vitro: Relevance for major depression and human hippocampal neurogenesis. Int J Neuropsychopharmacol 23:738-750.)
Treatment	Paroxetine	Oligodendrocytes	Examined the risk of neurotoxicity caused by SSRI medication; iPSC derived oligodendrocytes were exposed to MDD treatment paroxetine	-Reduction in neurite outgrowth -Cell population decrease	Zhong et al. (2020Zhong X, Harris G, Smirnova L, Zufferey V, Sá RDCDSE, Baldino Russo F, Baleeiro Beltrao Braga PC, Chesnut M, Zurich M-G, Hogberg HT et al. (2020) Antidepressant paroxetine exerts developmental neurotoxicity in an iPSC-derived 3D human brain model. Front Cell Neurosci 14:e25.)
Treatment	Bupropion	Cortical neurons	Examined the effects of bupropion on cortical neurons derived from MDD bupropion responders compared to a controlled group	-Cortical neurons derived from MDD patients showed a difference in synaptic connection, gene expression and morphology	Avior et al. (2021Avior Y, Ron S, Kroitorou D, Albeldas C, Lerner V, Corneo B, Nitzan E, Laifenfeld D and Cohen Solal T (2021) Depression patient-derived cortical neurons reveal potential biomarkers for antidepressant response. Transl Psychiatry 11:e201.)
Exploratory	N/a	Glial cells	Explored the effects of chronic cortisol exposure on glial cells from MDD patients	-Differentially expressed genes related to ion homeostasis, G-protein-coupled receptors (GPCR), and synaptic signaling	Heard et al. (2021Heard KJ, Shokhirev MN, Becronis C, Fredlender C, Zahid N, Le AT, Ji Y, Skime M, Nelson T, Hall-Flavin D et al. (2021) Chronic cortisol differentially impacts stem cell-derived astrocytes from major depressive disorder patients. Transl Psychiatry 11:e608.)
Exploratory	N/a	Neurons	Examined neurons derived from MDD patients and compared them to a control	-MDD patient derived neurons demonstrated functional and bioenergetic differences -Increased electrical activity -Change in sodium ion channels	Triebelhorn et al. (2022Triebelhorn J, Cardon I, Kuffner K, Bader S, Jahner T, Meindl K, Rothhammer-Hampl T, Riemenschneider MJ, Drexler K, Berneburg M et al. (2022) Induced neural progenitor cells and iPS-neurons from major depressive disorder patients show altered bioenergetics and electrophysiological properties. Mol Psychiatry. DOI: 10.1038/s41380-022-01660-1. https://doi.org/10.1038/s41380-022-01660... )
Exploratory	N/a	Forebrain organoids	Examined the difference in morphology, behavior, and function of corticoid organoids derived from MDD patients with a history of attempted suicide	-GABAergic interneurons and ventral forebrain organoids form MDD patients exhibited an increase in neuronal firing -Difference in neuronal morphology -Decrease in calcium signals -The dysregulation in neuronal morphology and behavior may be due to the decreased expression of 5-HT2C, a serotonergic receptor	Lu et al. (2023Lu K, Hong Y, Tao M, Shen L, Zheng Z, Fang K, Yuan F, Xu M, Wang C, Zhu D et al. (2023) Depressive patient‐derived GABA interneurons reveal abnormal neural activity associated with HTR2C. EMBO Mol Med 15:e16364.)

[1] Send correspondence to Maria Carolina Marchetto. University of California San Diego, Department of Anthropology, 9500 Gilman Drive, MC 0532, La Jolla, CA, USA. E-mail: mcmarchetto@ucsd.edu.

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Brasil

Exploring mood disorders and treatment options using human stem cells

Abstract