Transplantation of mesenchymal stem cells causes long-term alleviation of schizophrenia-like behaviour coupled with increased neurogenesis

Gobshtis, Nikolai; Tfilin, Matanel; Fraifeld, Vadim E.; Turgeman, Gadi

doi:10.1038/s41380-019-0623-x

Cited by 14 publications

(11 citation statements)

References 52 publications

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“…We found that a single intravenous injection (8 µg) of IL-17A to naïve ICR mice resulted in improved spatial learning [23]. Furthermore, in a murine model for schizophrenia treated with mesenchymal stem cells, long term improved social behavior was achieved and was significantly correlated with increased hippocampal expression of IL-17 [48]. Indeed, it was recently reported that schizophrenia patients in remission following therapy had improved cognitive functions that were positively correlated with IL-17 serum levels [49].…”

Section: Discussionmentioning

confidence: 89%

“…While IL-17A expression is known to be regulated by NOTCH signaling, it was recently reported that it can activate NOTCH signaling as well [51]. Similarly, in the murine schizophrenia model treated with mesenchymal stem cells, long term improvement in social behavior was also positively correlated with the NOTCH ligand Dll1 gene expression in the hippocampus [48]. Indeed, Hes1 gene expression in mature neurons is important for maintaining behavior [52].…”

Section: Discussionmentioning

confidence: 97%

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Interleukine-17 Modulates Neurogenesis and Behavior Following Exposure to Trauma in Mice

Willinger

Turgeman

2022

Cells

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Post-traumatic stress disorder (PTSD) is a psychiatric disorder accompanied by deficits in cognitive and social skills. Adult hippocampal neurogenesis is a lifelong phenomenon, with new neurons being formed in the granular cell layer of the dentate gyrus. Impaired neurogenesis is associated with multiple behavioral disorders including Alzheimer’s disease and schizophrenia. PTSD patients often present hippocampal atrophy and animal models clearly present impaired neurogenesis. Previous studies on PTSD patients demonstrated elevated levels of Th17 cells and plasma levels of the pro-inflammatory cytokine interleukin-17A (IL-17A). Since IL-17A can impair neurogenesis in mice, we thus hypothesized that decreasing the serum levels of IL-17A will increase hippocampal neurogenesis and alleviate symptoms in a murine model of PTSD. Surprisingly, our results showed that attempting to neutralize IL-17A with an antibody resulted in increased serum levels of IL-17A, while targeting IL-23, the upstream regulator of IL-17, did lower the levels of IL-17A in trauma-exposed mice. As expected, increased levels of serum IL-17A (in anti-IL-17A treated mice) resulted in impaired neurogenesis, reflected by reduced number of proliferating Ki67+ neural progenitors and newly formed DCX+ neurons, which was correlated with increased expression of HES1. Nevertheless, increased maturation was noted by the expression of SLIT2 and ACHE. In contrast, treatment with anti-IL-23 indeed resulted in increased neurogenesis. Behaviorally, both treatments did not affect trauma-related freezing behavior but did affect trauma-related social deficits. Unexpectedly, increased levels of serum IL-17A (in anti-IL-17A treated mice) prevented social deficits in trauma-exposed mice while anti-IL-23 exacerbated these deficits. We thus conclude that IL-17 is involved in regulating neurogenesis following exposure to stress but may be important in maintaining social behavior.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 97%

Interleukine-17 Modulates Neurogenesis and Behavior Following Exposure to Trauma in Mice

Willinger

Turgeman

2022

Cells

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“…MSCs also enhanced self-renewal and proliferation and differentiation of NPCs and suppressed inflammatory reaction by triggering the PI3K-Akt signal pathway [ 70 ]. Moreover, MSCs transplantation can increase adult hippocampal neurogenesis and improve schizophrenia-like behavioral phenotype [ 71 ]. In addition, interferon-γ (IFN-γ)-activated MSCs increased oligodendrogenesis and remyelination, inhibited microglial activation and microglial pro-inflammatory phenotype, and reduced infarct size by secreting nutritional factors, such as TGF-β and CX3CL1 [ 72 ].…”

Section: Potential Mechanisms and Therapeutic Targets Of Msc Transpla...mentioning

confidence: 99%

Potential mechanisms and therapeutic targets of mesenchymal stem cell transplantation for ischemic stroke

et al. 2022

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Ischemic stroke is one of the major causes of death and disability in the world. Currently, most patients cannot choose intravenous thrombolysis or intravascular mechanical thrombectomy because of narrow therapeutic windows and severe complications. Stem cell transplantation is an emerging treatment and has been studied in various central nervous system diseases. Animal and clinical studies showed that transplantation of mesenchymal stem cells (MSCs) could alleviate neurological deficits and bring hope for ischemic stroke treatment. This article reviewed biological characteristics, safety, feasibility and efficacy of MSCs therapy, potential therapeutic targets of MSCs, and production process of Good Manufacturing Practices-grade MSCs, to explore the potential therapeutic targets of MSCs in the process of production and use and provide new therapeutic directions for ischemic stroke.

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“…Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic modality for a variety of central nervous system disorders, including neurodegenerative disorders (e.g., Alzheimer’s [ 17 ] and Parkinson’s [ 18 ]), neuropsychiatric diseases (e.g., depression [ 19 , 20 ] and schizophrenia [ 21 ]), and peripheral pathologies [ 22 ]. MSCs migrate and home to injured regions, including the brain [ 23 ], in response to pathological sites’ pro-inflammatory signaling, which activates MSCs’ migratory tropism and adhesion capacity toward the distant, damaged tissue [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Placenta-Derived Mesenchymal-like Adherent Stromal Cells as an Effective Cell Therapy for Cocaine Addiction in a Rat Model

et al. 2022

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Recent research points to mesenchymal stem cells’ potential for treating neurological disorders, especially drug addiction. We examined the longitudinal effect of placenta-derived mesenchymal stromal-like cells (PLX-PAD) in a rat model for cocaine addiction. Sprague–Dawley male rats were trained to self-administer cocaine or saline daily until stable maintenance. Before the extinction phase, PLX-PAD cells were administered by intracerebroventricular or intranasal routes. Neurogenesis was evaluated, as was behavioral monitoring for craving. We labeled the PLX-PAD cells with gold nanoparticles and followed their longitudinal migration in the brain parallel to their infiltration of essential peripheral organs both by micro-CT and by inductively coupled plasma-optical emission spectrometry. Cell locations in the brain were confirmed by immunohistochemistry. We found that PLX-PAD cells attenuated cocaine-seeking behavior through their capacity to migrate to specific mesolimbic regions, homed on the parenchyma in the dentate gyrus of the hippocampus, and restored neurogenesis. We believe that intranasal cell therapy is a safe and effective approach to treating addiction and may offer a novel and efficient approach to rehabilitation.

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Transplantation of mesenchymal stem cells causes long-term alleviation of schizophrenia-like behaviour coupled with increased neurogenesis

Cited by 14 publications

References 52 publications

Interleukine-17 Modulates Neurogenesis and Behavior Following Exposure to Trauma in Mice

Interleukine-17 Modulates Neurogenesis and Behavior Following Exposure to Trauma in Mice

Potential mechanisms and therapeutic targets of mesenchymal stem cell transplantation for ischemic stroke

Placenta-Derived Mesenchymal-like Adherent Stromal Cells as an Effective Cell Therapy for Cocaine Addiction in a Rat Model

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