Antidepressant effect of stem cell-derived monoaminergic grafts

Cunningham, Miles G.; Donalds, Rachael A.; Carlezon, William A.; Hong, Sunghoi; Kim, Dae Sung; Kim, Dong Wook; Kim, Kwang S.

doi:10.1097/wnr.0b013e3282f0eb1c

Cited by 3 publications

(3 citation statements)

References 20 publications

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“…The forced swim test, a conventional assay for assessment of FSL rat depressive-like behavior, 25,60 showed a significant reduction in immobility time after MSC treatment. Similarly, it was previously shown that monoaminergic grafts originating from embryonic stem cells decreased the immobility duration in forced swim tests after engraftment to the prefrontal cortex of Sprague-Dawley rats 61 . We also applied the dominant-submissive social behavior paradigm, in which the relative behavioral tendency toward submissiveness or dominance reflects the behavioral status on the axis between depression and mania.…”

Section: Discussionsupporting

confidence: 59%

Mesenchymal stem cells increase hippocampal neurogenesis and counteract depressive-like behavior

et al. 2009

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Adult bone marrow-derived mesenchymal stem cells (MSCs) are regarded as potential candidates for treatment of neurodegenerative disorders, because of their ability to promote neurogenesis. MSCs promote neurogenesis by differentiating into neural lineages as well as by expressing neurotrophic factors that enhance the survival and differentiation of neural progenitor cells. Depression has been associated with impaired neurogenesis in the hippocampus and dentate gyrus. Therefore, the aim of this study was to analyze the therapeutic potential of MSCs in the Flinders sensitive line (FSL), a rat animal model for depression. Rats received an intracerebroventricular injection of culture-expanded and 1,1 0 -dioctadecyl-3,3,3 0 ,3 0 -tetramethylindocarbocyanine perchlorate (DiI)-labeled bone marrow-derived MSCs (10 5 cells). MSC-transplanted FSL rats showed significant improvement in their behavioral performance, as measured by the forced swim test and the dominant-submissive relationship (DSR) paradigm. After transplantation, MSCs migrated mainly to the ipsilateral dentate gyrus, CA1 and CA3 regions of the hippocampus, and to a lesser extent to the thalamus, hypothalamus, cortex and contralateral hippocampus. Neurogenesis was increased in the ipsilateral dentate gyrus and hippocampus of engrafted rats (granular cell layer) and was correlated with MSC engraftment and behavioral performance. We therefore postulate that MSCs may serve as a novel modality for treating depressive disorders.

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Section: Discussionsupporting

confidence: 59%

Mesenchymal stem cells increase hippocampal neurogenesis and counteract depressive-like behavior

et al. 2009

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“…Although affective neural networks are integrated with movement networks, analysis of graft effects on emotion is only beginning to be investigated. Our laboratory recently demonstrated in animal models that grafts of genetically-customized monoaminergic neurons can have an antidepressant effect and thus may be capable of modulating corticolimbic circuitry [2]. The present experiments demonstrate that a similar approach is feasible to study the neural circuitry associated with fear and anxiety.…”

Section: Discussionmentioning

confidence: 53%

Amygdalar GABAergic-rich neural grafts attenuate anxiety-like behavior in rats

Cunningham

connor

Carlezon

et al. 2009

Behavioural Brain Research

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Transplantation experiments have shown that neurologic deficits may be reversed by engrafting fresh tissue or engineered cells within dysfunctional neural circuitry. In experimental and clinical settings, this approach has provided insights into the pathology and treatment of neurologic diseases, primarily movement disorders. The present experiments were designed to investigate whether a similar strategy is feasible as a method to investigate, and perhaps repair, circuitry integral to emotional disorders. We focused on the amygdala, a macrostructure known to be involved in the expression of anxiety- and fear-related behaviors. GABAergic cell-rich suspensions were prepared from E17 rat lateral ganglionic eminence and engrafted bilaterally into the lateral and basolateral amygdaloid nuclei of young adult rats. After six weeks, increased numbers of GABAergic neurons were identified in the vicinity of the graft sites, and electron microscopy provided evidence for functional integration of transplanted cells. Rats with these grafts spent more time in the open arms of the elevated plus maze, consistent with an anxioloytic-like phenotype. These rats were also less sensitive to the unconditioned anxiogenic effects of light on the acoustic startle response, although fear-potentiated startle was not affected, suggesting that the grafts produced an attenuation of unlearned fear but did not affect acquisition of conditioned fear. Our results raise the possibility that distinct components of emotion can be modulated by strategic neural engraftment.

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“…With the advent of stem cell technology, the potential to replace injured or degenerative neurons needs to be explored. Several recent successes have encouraged further effort (Cunningham, et al 2007; Ren-Patterson, et al 2005; Vazey, et al 2006). …”

Section: Discussionmentioning

confidence: 99%

Expression profile of differentiating serotonin neurons derived from rhesus embryonic stem cells and comparison to adult serotonin neurons

Bethea

Reddy

Pedersen

et al. 2009

Gene Expression Patterns

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The rhesus monkey embryonic stem cell line 366.4 differentiates into serotonin neurons. We examined the genetic cascade during differentiation and compared ESC-derived serotonin neurons to adult monkey serotonin neurons. RNA was extracted from ESC colonies, embryoid bodies (EBs), neurospheres in selection (N1) and proliferation stages (N2), differentiated serotonin neurons (N3) and from laser captured (LC) serotonin neurons of spayed female macaques treated with placebo, estrogen (E), progesterone (P) or E+P. The RNA was labeled and hybridized to Rhesus Monkey Affymetrix Gene Chips (n=1 per stage and 2 per animal treatment). Gene expression was examined with GeneSifter software. 545 genes that were related to developmental processes showed a 3-fold or greater change between stages. TGFβ, Wnt, VEGF and Hedgehog signaling pathways showed the highest percent of probe set changes during differentiation. Genes in the categories (a) homeobox binding and transcription factors, (b) growth factors and receptors, (c) brain and neural specific factors and (d) serotonin specific factors are reported. Pivotal genes were confirmed with quantitative RT-PCR. In the serotonin developmental cascade, FGFR2 was robustly expressed at each stage. GATA3 was robustly expressed in EBs. Sonic hedgehog (Shh), PTCH (Shh-R), and Fev1 transcription factor expression coincided with the induction of serotonin specific marker genes during N1-selection. A majority of the examined genes were expressed in adult serotonin neurons. However, in the ESC-derived neurons, there was significant over-representation of probe sets related to cell cycle, axon guidance & dorso-ventral axis formation. This analysis suggests that the 366.4 cell line possesses cues for serotonin differentiation at early stages of differentiation, but that ESC-derived serotonin neurons are still immature.

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Antidepressant effect of stem cell-derived monoaminergic grafts

Cited by 3 publications

References 20 publications

Mesenchymal stem cells increase hippocampal neurogenesis and counteract depressive-like behavior

Mesenchymal stem cells increase hippocampal neurogenesis and counteract depressive-like behavior

Amygdalar GABAergic-rich neural grafts attenuate anxiety-like behavior in rats

Expression profile of differentiating serotonin neurons derived from rhesus embryonic stem cells and comparison to adult serotonin neurons

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