Neurocircuitry of stress: central control of the hypothalamo–pituitary–adrenocortical axis

https://arep.med.harvard.edu/pdf/Wichterle02.pdf

Directed Differentiation of Embryonic Stem Cells into Motor Neurons

Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development.

Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness.

Recent studies suggest that cancer can arise from a cancer stem cell (CSC), a tumor-initiating cell that has properties similar to those of stem cells. CSCs have been identified in several malignancies, including those of blood, brain, and breast. Here, we test whether stem cell-like populations exist in human melanomas. In approximately 20% of the metastatic melanomas cultured in growth medium suitable for human embryonic stem cells, we found a subpopulation of cells propagating as nonadherent spheres, whereas in standard medium, adherent monolayer cultures were established. Individual cells from melanoma spheres (melanoma spheroid cells) could differentiate under appropriate conditions into multiple cell lineages, such as melanocytic, adipocytic, osteocytic, and chondrocytic lineages, which recapitulates the plasticity of neural crest stem cells. Multipotent melanoma spheroid cells persisted after serial cloning in vitro and transplantation in vivo, indicating their ability to self-renew. Furthermore, they were more tumorigenic than adherent cells when grafted to mice. We identified similar multipotent spheroid cells in melanoma cell lines and found that the stem cell population was enriched in a CD20+ fraction of melanoma cells. Based on these findings, we propose that melanomas can contain a subpopulation of stem cells that contribute to heterogeneity and tumorigenesis. Targeting this population may lead to effective treatments for melanomas.

https://cancerres.aacrjournals.org/content/canres/65/20/9328.full.pdf

A tumorigenic subpopulation with stem cell properties in melanomas.

The derivation of neural progenitor cells from human embryonic stem (ES) cells is of value both in the study of early human neurogenesis and in the creation of an unlimited source of donor cells for neural transplantation therapy. Here we report the generation of enriched and expandable preparations of proliferating neural progenitors from human ES cells. The neural progenitors could differentiate in vitro into the three neural lineages--astrocytes, oligodendrocytes, and mature neurons. When human neural progenitors were transplanted into the ventricles of newborn mouse brains, they incorporated in large numbers into the host brain parenchyma, demonstrated widespread distribution, and differentiated into progeny of the three neural lineages. The transplanted cells migrated along established brain migratory tracks in the host brain and differentiated in a region-specific manner, indicating that they could respond to local cues and participate in the processes of host brain development. Our observations set the stage for future developments that may allow the use of human ES cells for the treatment of neurological disorders.

Neural progenitors from human embryonic stem cells.

Human embryonic stem cells (hESCs) may potentially serve as a renewable source of cells for transplantation. In Parkinson's disease, hESC-derived dopaminergic (DA) neurons may replace the degenerated neurons in the brain. Here, we generated highly enriched cultures of neural progenitors from hESCs and grafted the progenitors into the striatum of Parkinsonian rats. The grafts survived for at least 12 weeks, the transplanted cells stopped proliferating, and teratomas were not observed. The grafted cells differentiated in vivo into DA neurons, though at a low prevalence similar to that observed following spontaneous differentiation in vitro. Transplanted rats exhibited a significant partial correction of D-amphetamine and apomorphine-induced rotational behavior, along with a significant improvement in stepping and placing non-pharmacological behavioral tests. While transplantation of uncommitted hESC-derived neural progenitors induced partial behavioral recovery, our data indicate that the host-lesioned striatum could not direct the transplanted neural progenitors to acquire a dopaminergic fate. Hence, induction of their differentiation toward a midbrain fate prior to transplantation is probably required for complete correction of behavioral deficit. Our observations encourage further developments for the potential use of hESCs in the treatment of Parkinson's disease.

Transplantation of human embryonic stem cell-derived neural progenitors improves behavioral deficit in Parkinsonian rats.

Differential effect of amygdaloid lesions on CRF-41, ACTH and corticosterone responses following neural stimuli.

Halofuginone inhibits angiogenesis and growth in implanted metastatic rat brain tumor model--an MRI study.

The amygdala is known to modulate the function of the hypothalamo-pituitary-adrenocortical (HPA) axis, but the mechanism of this effect is still not clear. In the present study we examined the specifi

The amygdala regulates the pituitary-adrenocortical response and release of hypothalamic serotonin following electrical stimulation of the dorsal raphe nucleus in the rat.

Anna Itzik

Papers

Neural progenitors from human embryonic stem cells.

Transplantation of human embryonic stem cell-derived neural progenitors improves behavioral deficit in Parkinsonian rats.

Differential effect of amygdaloid lesions on CRF-41, ACTH and corticosterone responses following neural stimuli.

Halofuginone inhibits angiogenesis and growth in implanted metastatic rat brain tumor model--an MRI study.

The amygdala regulates the pituitary-adrenocortical response and release of hypothalamic serotonin following electrical stimulation of the dorsal raphe nucleus in the rat.