Commentary

Could stem cells have a role in treating mental illnesses?

Current Psychiatry. 2021 December;20(12):35-41 | doi: 10.12788/cp.0192

References

Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861-872.
Duncan T, Valenzuela M. Alzheimer’s disease, dementia, and stem cell therapy. Stem Cell Res Ther. 2017;8(1):111.
Brinton RD, Wang JM. Therapeutic potential of neurogenesis for prevention and recovery from Alzheimer’s disease: allopregnanolone as a proof of concept neurogenic agent. Curr Alzheimer Res. 2006;3(3):185-190.
Taupin P. Adult neurogenesis, neural stem cells, and Alzheimer’s disease: developments, limitations, problems, and promises. Curr Alzheimer Res. 2009;6(6):461-470.
Taupin P. Neurogenesis, NSCs, pathogenesis, and therapies for Alzheimer’s disease. Front Biosci (Schol Ed). 2011;3:178-90.
Kang JM, Yeon BK, Cho SJ, et al. Stem cell therapy for Alzheimer’s disease: a review of recent clinical trials. J Alzheimers Dis. 2016;54(3):879-889.
Li M, Guo K, Ikehara S. Stem cell treatment for Alzheimer’s disease. Int J Mol Sci. 2014;15(10):19226-19238.
Zappa Villar MF, López Hanotte J, Pardo J, et al. Mesenchymal stem cells therapy improved the streptozotocin-induced behavioral and hippocampal impairment in rats. Mol Neurobiol. 2020;57(2):600-615.
Lupien SJ, de Leon M, de Santi S, et al. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat Neurosci. 1998;1(1):69-73.
Iannitelli A, Quartini A, Tirassa P, et al. Schizophrenia and neurogenesis: a stem cell approach. Neurosci Biobehav Rev. 2017;80:414-442.
Sacco R, Cacci E, Novarino G. Neural stem cells in neuropsychiatric disorders. Curr Opin Neurobiol. 2018; 48:131-138.
Miller ND, Kelsoe JR. Unraveling the biology of bipolar disorder using induced pluripotent stem-derived neurons. Bipolar Disord. 2017;19(7):544-551.
O’Shea KS, McInnis MG. Neurodevelopmental origins of bipolar disorder: iPSC models. Mol Cell Neurosci. 2016;73:63-83.
Jacobs BM. A dangerous method? The use of induced pluripotent stem cells as a model for schizophrenia. Schizophr Res. 2015;168(1-2):563-568.
Liu Y, Deng W. Reverse engineering human neurodegenerative disease using pluripotent stem cell technology. Brain Res. 2016;1638(Pt A):30-41.
Siniscalco D, Kannan S, Semprún-Hernández N, et al. Stem cell therapy in autism: recent insights. Stem Cells Cloning. 2018;11:55-67.
Siniscalco D, Bradstreet JJ, Sych N, et al. Mesenchymal stem cells in treating autism: novel insights. World J Stem Cells. 2014;6(2):173-178.
Siniscalco D, Sapone A, Cirillo A, et al. Autism spectrum disorders: is mesenchymal stem cell personalized therapy the future? J Biomed Biotechnol. 2012; 2012:480289.
Bradstreet JJ, Sych N, Antonucci N, et al. Efficacy of fetal stem cell transplantation in autism spectrum disorders: an open-labeled pilot study. Cell Transplant. 2014;23(Suppl 1):S105-S112.
Lv YT, Zhang Y, Liu M, et al. Transplantation of human cord blood mononuclear cells and umbilical cordderived mesenchymal stem cells in autism. J Transl Med. 2013;11:196.
Vargas DL, Nascimbene C, Krishnan C, et al. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57(1):67-81.
Wei L, Keogh CL, Whitaker VR, et al. Angiogenesis and stem cell transplantation as potential treatments of cerebral ischemic stroke. Pathophysiology. 2005;12(1): 47-62.
Newman MB, Willing AE, Manresa JJ, et al. Cytokines produced by cultured human umbilical cord blood (HUCB) cells: implications for brain repair. Exp Neurol. 2006;199(1):201-218.
Peterson DA. Umbilical cord blood cells and brain stroke injury: bringing in fresh blood to address an old problem. J Clin Invest. 2004;114(3):312-314.
Cohly HH, Panja A. Immunological findings in autism. Int Rev Neurobiol. 2005;71:317-341.
Ashwood P, Van de Water J. Is autism an autoimmune disease? Autoimmun Rev. 2004;3(7-8):557-562.
Yagi H, Soto-Gutierrez A, Parekkadan B, et al. Mesenchymal stem cells: mechanisms of immunomodulation and homing. Cell Transplant. 2010;19(6):667-679.
Vaccarino FM, Urban AE, Stevens HE, et al. Annual Research Review: The promise of stem cell research for neuropsychiatric disorders. J Child Psychol Psychiatry. 2011;52(4):504-516.
Liu EY, Scott CT. Great expectations: autism spectrum disorder and induced pluripotent stem cell technologies. Stem Cell Rev Rep. 2014;10(2):145-150.
Richardson-Jones JW, Craige CP, Guiard BP, et al. 5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants. Neuron. 2010;65(1):40-52.
Saarelainen T, Hendolin P, Lucas G, et al. Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci. 2003;23(1):349-357.
Klumpers UM, Veltman DJ, Drent ML, et al. Reduced parahippocampal and lateral temporal GABAA-[11C] flumazenil binding in major depression: preliminary results. Eur J Nucl Med Mol Imaging. 2010;37(3): 565-574.
Bremner JD, Narayan M, Anderson ER, et al. Hippocampal volume reduction in major depression. Am J Psychiatry. 2000;157(1):115-118.
Bremner JD, Randall P, Scott TM, et al. MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry. 1995;152(7):973-981.
Vincent SL, Todtenkopf MS, Benes FM. A comparison of the density of pyramidal and non-pyramidal neurons in the anterior cingulate cortex of schizophrenics and manic depressives. Soc Neurosci Abstr. 1997;23:2199.
Benes FM, Kwok EW, Vincent SL, et al. A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives. Biol Psychiatry. 1998;44(2): 88-97.
Ongür D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci U S A. 1998;95(22):13290-13295.
Rajkowska G, Miguel-Hidalgo JJ, Wei J, et al. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry. 1999;45(9): 1085-1098.
Licinio J, Wong ML. Serotonergic neurons derived from induced pluripotent stem cells (iPSCs): a new pathway for research on the biology and pharmacology of major depression. Mol Psychiatry. 2016;21(1):1-2.
Chen SK, Tvrdik P, Peden E, et al. Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell. 2010;141(5):775-785.
Israel Y, Ezquer F, Quintanilla ME, et al. Intracerebral stem cell administration inhibits relapse-like alcohol drinking in rats. Alcohol Alcohol. 2017;52(1):1-4.
Ezquer F, Morales P, Quintanilla ME, et al. Intravenous administration of anti-inflammatory mesenchymal stem cell spheroids reduces chronic alcohol intake and abolishes binge-drinking. Sci Rep. 2018;8(1):4325.
Scarnati MS, Halikere A, Pang ZP. Using human stem cells as a model system to understand the neural mechanisms of alcohol use disorders: current status and outlook. Alcohol. 2019;74:83-93.
Yadid GM, Popovtzer R. Nanoparticle-mesenchymal stem cell conjugates for cell therapy in drug addiction. NIH grant application. 2017.
Xu C, Loh HH, Law PY. Effects of addictive drugs on adult neural stem/progenitor cells. Cell Mol Life Sci. 2016;73(2):327-348.
Dholakiya SL, Aliberti A, Barile FA. Morphine sulfate concomitantly decreases neuronal differentiation and opioid receptor expression in mouse embryonic stem cells. Toxicol Lett. 2016;247:45-55.
Zhang Y, Loh HH, Law PY. Effect of opioid on adult hippocampal neurogenesis. Scientific World Journal. 2016;2016:2601264.
Bortolotto V, Grilli M. Opiate analgesics as negative modulators of adult hippocampal neurogenesis: potential implications in clinical practice. Front Pharmacol. 2017; 8:254.
Galve-Roperh I, Chiurchiù V, Díaz-Alonso J, et al. Cannabinoid receptor signaling in progenitor/stem cell proliferation and differentiation. Prog Lipid Res. 2013; 52(4):633-650.
Zimmermann T, Maroso M, Beer A, et al. Neural stem cell lineage-specific cannabinoid type-1 receptor regulates neurogenesis and plasticity in the adult mouse hippocampus. Cereb Cortex. 2018;28(12):4454-4471.
Ren J, Liu N, Sun N, et al. Mesenchymal stem cells and their exosomes: promising therapies for chronic pain. Curr Stem Cell Res Ther. 2019;14(8):644-653.

Stem cells as a treatment for mental illness

Based on our understanding of the function of stem cells, many neurodegenerative-, vascular-, immune-, and inflammation-based psychiatric conditions can be influenced by stem cell treatment. Here I review the potential therapeutic role of stem cells in the treatment of several psychiatric disorders.

Alzheimer’s dementia

Alzheimer’s dementia (AD) is a progressive neurodegenerative pathology based on neuronal and synaptic loss. Repopulation and regeneration of depleted neuronal circuitry by exogenous stem cells may be a rational therapeutic strategy.² The regeneration of lost neurons has the potential to restore cognitive function. Multiple growth factors that regulate neurogenesis are abundant during child development but dramatically decline with age. The introduction of stem cells—especially those derived from newborn waste—seem to promote recovery from neurodegenerative disease or injury.³

There currently is no cure for AD. Cellular therapy promises new advances in treatment.⁴ Neurogenesis occurs not only during fetal development but in the adult brain. Neural stem cells reside in the adult CNS of all mammals.⁵ They are intimately involved in continuous restoration, but age just like the rest of the animal tissue, providing ever-decreasing restorative potential.

The number of studies of stem cells in AD has increased since the early 2000 s,^6,7 and research continues to demonstrate robust CNS neurogenesis. In a 2020 study, Zappa Villar et al⁸ evaluated stem cells as a treatment for rats in which an AD model was induced by the intracerebroventricular injection of streptozotocin (STZ). The STZ-treated rats displayed poor performance in all behavioral tests. Stem cell therapy increased exploratory behavior, decreased anxiety, and improved spatial memory and marble-burying behavior; the latter was representative of daily life activities. Importantly, stem cell therapy ameliorated and restored hippocampal atrophy and some presynaptic protein levels in the rats with AD.⁸ Animal models cannot be automatically applied to humans, but they shine a light on the areas that need further exploration.

In humans, elevated cortisol levels during aging predict hippocampal atrophy and memory deficits,⁹ and this deficiency may be positively influenced by stem cell treatment.

Schizophrenia

Recent research indicates that schizophrenia may begin with abnormal neurogenesis from neural stem cells inside the embryo, and that this process may be particularly vulnerable to numerous genetic and/or environmental disturbances of early brain development.¹⁰ Because neurogenesis is not confined to the womb but is a protracted process that continues into postnatal life, adolescence and beyond, influencing this process may be a way to add to the schizophrenia treatment armamentarium.¹⁰ Sacco et al¹¹ described links between the alteration of intrauterine and adult neurogenesis and the causes of neuropsychiatric disorders, including schizophrenia. Immune and inflammatory mechanisms are important in the etiology of schizophrenia. By their core function, stem cells address both mechanisms, and may directly modulate this devastating disease.

In addition to clinical hopes, advances in research tools hold the promise of new discoveries. With the advent of iPSC technology, it is possible to generate live neurons in vitro from somatic tissue of patients with schizophrenia. Despite its many limitations, this revolutionary technology has already helped to advance our understanding of schizophrenia.¹¹

Bipolar disorder

Many of the fundamental neurobiological mechanisms of schizophrenia are mirrored in bipolar disorder.¹² Though we are not ready to bring stem cells into the day-to-day treatment of this condition, several groups are starting to apply iPSC technology to the study of bipolar disorder.¹³

Neurodevelopmental factors—particularly pathways related to nervous system development, cell migration, extracellular matrix, methylation, and calcium signaling—have been identified in large gene expression studies as altered in bipolar disorder.¹⁴ Stem cell technology opens doorways to reverse engineering of human neurodegenerative disease.¹⁵

Continue to: Autism spectrum disorders...

References

Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861-872.
Duncan T, Valenzuela M. Alzheimer’s disease, dementia, and stem cell therapy. Stem Cell Res Ther. 2017;8(1):111.
Brinton RD, Wang JM. Therapeutic potential of neurogenesis for prevention and recovery from Alzheimer’s disease: allopregnanolone as a proof of concept neurogenic agent. Curr Alzheimer Res. 2006;3(3):185-190.
Taupin P. Adult neurogenesis, neural stem cells, and Alzheimer’s disease: developments, limitations, problems, and promises. Curr Alzheimer Res. 2009;6(6):461-470.
Taupin P. Neurogenesis, NSCs, pathogenesis, and therapies for Alzheimer’s disease. Front Biosci (Schol Ed). 2011;3:178-90.
Kang JM, Yeon BK, Cho SJ, et al. Stem cell therapy for Alzheimer’s disease: a review of recent clinical trials. J Alzheimers Dis. 2016;54(3):879-889.
Li M, Guo K, Ikehara S. Stem cell treatment for Alzheimer’s disease. Int J Mol Sci. 2014;15(10):19226-19238.
Zappa Villar MF, López Hanotte J, Pardo J, et al. Mesenchymal stem cells therapy improved the streptozotocin-induced behavioral and hippocampal impairment in rats. Mol Neurobiol. 2020;57(2):600-615.
Lupien SJ, de Leon M, de Santi S, et al. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat Neurosci. 1998;1(1):69-73.
Iannitelli A, Quartini A, Tirassa P, et al. Schizophrenia and neurogenesis: a stem cell approach. Neurosci Biobehav Rev. 2017;80:414-442.
Sacco R, Cacci E, Novarino G. Neural stem cells in neuropsychiatric disorders. Curr Opin Neurobiol. 2018; 48:131-138.
Miller ND, Kelsoe JR. Unraveling the biology of bipolar disorder using induced pluripotent stem-derived neurons. Bipolar Disord. 2017;19(7):544-551.
O’Shea KS, McInnis MG. Neurodevelopmental origins of bipolar disorder: iPSC models. Mol Cell Neurosci. 2016;73:63-83.
Jacobs BM. A dangerous method? The use of induced pluripotent stem cells as a model for schizophrenia. Schizophr Res. 2015;168(1-2):563-568.
Liu Y, Deng W. Reverse engineering human neurodegenerative disease using pluripotent stem cell technology. Brain Res. 2016;1638(Pt A):30-41.
Siniscalco D, Kannan S, Semprún-Hernández N, et al. Stem cell therapy in autism: recent insights. Stem Cells Cloning. 2018;11:55-67.
Siniscalco D, Bradstreet JJ, Sych N, et al. Mesenchymal stem cells in treating autism: novel insights. World J Stem Cells. 2014;6(2):173-178.
Siniscalco D, Sapone A, Cirillo A, et al. Autism spectrum disorders: is mesenchymal stem cell personalized therapy the future? J Biomed Biotechnol. 2012; 2012:480289.
Bradstreet JJ, Sych N, Antonucci N, et al. Efficacy of fetal stem cell transplantation in autism spectrum disorders: an open-labeled pilot study. Cell Transplant. 2014;23(Suppl 1):S105-S112.
Lv YT, Zhang Y, Liu M, et al. Transplantation of human cord blood mononuclear cells and umbilical cordderived mesenchymal stem cells in autism. J Transl Med. 2013;11:196.
Vargas DL, Nascimbene C, Krishnan C, et al. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57(1):67-81.
Wei L, Keogh CL, Whitaker VR, et al. Angiogenesis and stem cell transplantation as potential treatments of cerebral ischemic stroke. Pathophysiology. 2005;12(1): 47-62.
Newman MB, Willing AE, Manresa JJ, et al. Cytokines produced by cultured human umbilical cord blood (HUCB) cells: implications for brain repair. Exp Neurol. 2006;199(1):201-218.
Peterson DA. Umbilical cord blood cells and brain stroke injury: bringing in fresh blood to address an old problem. J Clin Invest. 2004;114(3):312-314.
Cohly HH, Panja A. Immunological findings in autism. Int Rev Neurobiol. 2005;71:317-341.
Ashwood P, Van de Water J. Is autism an autoimmune disease? Autoimmun Rev. 2004;3(7-8):557-562.
Yagi H, Soto-Gutierrez A, Parekkadan B, et al. Mesenchymal stem cells: mechanisms of immunomodulation and homing. Cell Transplant. 2010;19(6):667-679.
Vaccarino FM, Urban AE, Stevens HE, et al. Annual Research Review: The promise of stem cell research for neuropsychiatric disorders. J Child Psychol Psychiatry. 2011;52(4):504-516.
Liu EY, Scott CT. Great expectations: autism spectrum disorder and induced pluripotent stem cell technologies. Stem Cell Rev Rep. 2014;10(2):145-150.
Richardson-Jones JW, Craige CP, Guiard BP, et al. 5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants. Neuron. 2010;65(1):40-52.
Saarelainen T, Hendolin P, Lucas G, et al. Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci. 2003;23(1):349-357.
Klumpers UM, Veltman DJ, Drent ML, et al. Reduced parahippocampal and lateral temporal GABAA-[11C] flumazenil binding in major depression: preliminary results. Eur J Nucl Med Mol Imaging. 2010;37(3): 565-574.
Bremner JD, Narayan M, Anderson ER, et al. Hippocampal volume reduction in major depression. Am J Psychiatry. 2000;157(1):115-118.
Bremner JD, Randall P, Scott TM, et al. MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry. 1995;152(7):973-981.
Vincent SL, Todtenkopf MS, Benes FM. A comparison of the density of pyramidal and non-pyramidal neurons in the anterior cingulate cortex of schizophrenics and manic depressives. Soc Neurosci Abstr. 1997;23:2199.
Benes FM, Kwok EW, Vincent SL, et al. A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives. Biol Psychiatry. 1998;44(2): 88-97.
Ongür D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci U S A. 1998;95(22):13290-13295.
Rajkowska G, Miguel-Hidalgo JJ, Wei J, et al. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry. 1999;45(9): 1085-1098.
Licinio J, Wong ML. Serotonergic neurons derived from induced pluripotent stem cells (iPSCs): a new pathway for research on the biology and pharmacology of major depression. Mol Psychiatry. 2016;21(1):1-2.
Chen SK, Tvrdik P, Peden E, et al. Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell. 2010;141(5):775-785.
Israel Y, Ezquer F, Quintanilla ME, et al. Intracerebral stem cell administration inhibits relapse-like alcohol drinking in rats. Alcohol Alcohol. 2017;52(1):1-4.
Ezquer F, Morales P, Quintanilla ME, et al. Intravenous administration of anti-inflammatory mesenchymal stem cell spheroids reduces chronic alcohol intake and abolishes binge-drinking. Sci Rep. 2018;8(1):4325.
Scarnati MS, Halikere A, Pang ZP. Using human stem cells as a model system to understand the neural mechanisms of alcohol use disorders: current status and outlook. Alcohol. 2019;74:83-93.
Yadid GM, Popovtzer R. Nanoparticle-mesenchymal stem cell conjugates for cell therapy in drug addiction. NIH grant application. 2017.
Xu C, Loh HH, Law PY. Effects of addictive drugs on adult neural stem/progenitor cells. Cell Mol Life Sci. 2016;73(2):327-348.
Dholakiya SL, Aliberti A, Barile FA. Morphine sulfate concomitantly decreases neuronal differentiation and opioid receptor expression in mouse embryonic stem cells. Toxicol Lett. 2016;247:45-55.
Zhang Y, Loh HH, Law PY. Effect of opioid on adult hippocampal neurogenesis. Scientific World Journal. 2016;2016:2601264.
Bortolotto V, Grilli M. Opiate analgesics as negative modulators of adult hippocampal neurogenesis: potential implications in clinical practice. Front Pharmacol. 2017; 8:254.
Galve-Roperh I, Chiurchiù V, Díaz-Alonso J, et al. Cannabinoid receptor signaling in progenitor/stem cell proliferation and differentiation. Prog Lipid Res. 2013; 52(4):633-650.
Zimmermann T, Maroso M, Beer A, et al. Neural stem cell lineage-specific cannabinoid type-1 receptor regulates neurogenesis and plasticity in the adult mouse hippocampus. Cereb Cortex. 2018;28(12):4454-4471.
Ren J, Liu N, Sun N, et al. Mesenchymal stem cells and their exosomes: promising therapies for chronic pain. Curr Stem Cell Res Ther. 2019;14(8):644-653.

Could stem cells have a role in treating mental illnesses?

References

Stem cells as a treatment for mental illness

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