The formation of the neurovascular unit, blood brain-barrier tracked in real-time for the first time.


Crucial bodily functions like heart rate, blood flow, breathing and digestion are regulated by the neurovascular unit. The neurovascular unit is made up of the blood–brain barrier, blood vessels, microglia and smooth muscles under the control of autonomic neurons. Yet how the nervous and vascular systems come together during development to coordinate these functions is not well understood.

Now, using human embryonic stem cells, researchers at University of California and Sanford-Burnham Medical Research Institute created a model that allows them to track cellular behaviour during the earliest stages of human development in real-time. The model reveals, for the first time, how autonomic neurons and blood vessels come together to form the neurovascular unit.  The opensource study is published in the journal Stem Cell Reports.

The team state that the new model allows the medical community to follow the fate of distinct cell types during development, as they work cooperatively, in a way that can’t be done in intact embryos, individual cell lines or mouse models. They go on to add that if researchers are ever going to use stem cells to develop new organ systems, they will need to know how different cell types come together to form complex and functional structures such as the neurovascular unit.

The team explain that capillary endothelial cells, the site of anatomical blood–brain barrier, neurons, and nonneuronal cells such as pericytes, astrocytes, microglia together constitute a functional unit, often referred to as a neurovascular unit.  The endothelial cells form the blood vessel (vascular) tube; smooth muscle cells cover the endothelial tube and control vascular tone; and the autonomic neurons influence the smooth muscle’s ability to contract and maintain vascular tone, all the while being regulated and protected by microglia.

The current study revealed that separate signals produced by endothelial cells and smooth muscle cells are required for embryonic cells to differentiate into autonomic neurons. The researchers discovered that endothelial cells secrete nitric oxide, while smooth muscle cells use the protein T-cadherin to interact with the neural crest, specialized embryonic cells that give rise to portions of the nervous system and other organs. The combination of endothelial cell nitric oxide and the T-cadherin interaction is sufficient to coax neural crest cells into becoming autonomic neurons, where they can then co-align with developing blood vessels.

In addition to answering long-standing questions about human development and improving the odds that scientists will one day be able to generate artificial organs from stem cells, the new data findings on the autonomic nervous system also has implications for rare inherited conditions such as neurofibromatosis, tuberous sclerosis and Hirschsprung’s disease.

The team surmise that these observations may help to explain certain human disease syndromes in which abnormalities of the nervous system appear to be associated, for previously unclear reasons, with vascular abnormalities.  The researchers conclude that modeling human development and disease in the lab must take into account multiple cell types in order to reflect the actual human condition, rather than examining pure populations of one cell type or another.

Source:  University of California, San Diego School of Medicine and Moores Cancer Center

 

To gain insight into the cellular and molecular cues that promote neurovascular co-patterning at the earliest stages of human embryogenesis, we developed a human embryonic stem cell model to mimic the developing epiblast. Contact of ectoderm-derived neural cells with mesoderm-derived vasculature is initiated via the neural crest (NC), not the neural tube (NT). Neurovascular co-patterning then ensues with specification of NC toward an autonomic fate requiring vascular endothelial cell (EC)-secreted nitric oxide (NO) and direct contact with vascular smooth muscle cells (VSMCs) via T-cadherin-mediated homotypic interactions. Once a neurovascular template has been established, NT-derived central neurons then align themselves with the vasculature. Our findings reveal that, in early human development, the autonomic nervous system forms in response to distinct molecular cues from VSMCs and ECs, providing a model for how other developing lineages might coordinate their co-patterning.  hESC Differentiation toward an Autonomic Neuronal Cell Fate Depends on Distinct Cues from the Co-Patterning Vasculature.  Cheresh et al 2015.

To gain insight into the cellular and molecular cues that promote neurovascular co-patterning at the earliest stages of human embryogenesis, we developed a human embryonic stem cell model to mimic the developing epiblast. Contact of ectoderm-derived neural cells with mesoderm-derived vasculature is initiated via the neural crest (NC), not the neural tube (NT). Neurovascular co-patterning then ensues with specification of NC toward an autonomic fate requiring vascular endothelial cell (EC)-secreted nitric oxide (NO) and direct contact with vascular smooth muscle cells (VSMCs) via T-cadherin-mediated homotypic interactions. Once a neurovascular template has been established, NT-derived central neurons then align themselves with the vasculature. Our findings reveal that, in early human development, the autonomic nervous system forms in response to distinct molecular cues from VSMCs and ECs, providing a model for how other developing lineages might coordinate their co-patterning. hESC Differentiation toward an Autonomic Neuronal Cell Fate Depends on Distinct Cues from the Co-Patterning Vasculature. Cheresh et al 2015.

 

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