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(ABOVE) Autonomic neurons (green) co-patterning with blood vessels (red) Image Credit: UC San Diego School of Medicine (BELOW) The autonomic nervous system forms in response to distinct molecular cues from VSMCs and ECs

Clues to how human neurovascular unit forms

Crucial functions we depend on but don't consciously think about — things like heart rate, blood flow, breathing and digestion — are regulated by our neurovascular unit (1) which is made up of blood vessels and smooth muscles. But how they work together to coordinate functions is not yet understood.

Using human embryonic stem cells, researchers at University of California, San Diego School of Medicine and Moores Cancer Center and Sanford-Burnham Medical Research Institute created a model that allows them to track cellular behavior 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 study is published May 21 by Stem Cell Reports.

"This new model allows us to follow the fate of distinct cell types during development, as they work cooperatively, in a way that we can't in intact embryos, individual cell lines or mouse models. And if we're ever going to use stem cells to develop new organ systems, we need to know how different cell types come together to form complex and functional structures such as the neurovascular unit."

David Cheresh PhD, co-senior author of the study, Distinguished Professor of Pathology, vice-chair for research and development and associate director for translational research at the Univercity of California, San Diego.

The neurovascular unit is made up of three cells types: 1. endothelial cells, which form the blood vessel (vascular) tube; 2. smooth muscle cells, which cover the endothelial tube and control vascular tone; and 3. autonomic neurons, which influence smooth muscle's ability to contract and maintain vascular tone.

The study revealed that separate signals produced by endothelial cells and smooth muscle cells are required for embryonic cells to differentiate into autonomic neurons. Researchers discovered that endothelial cells secrete nitric oxide, while smooth muscle cells use the protein T-cadherin to interact with neural crest cells, those specialized embryonic cells that give rise to portions of the nervous system and other organs.

The interaction of endothelial cell nitric oxide and the T-cadherin coaxes neural crest cells into becoming autonomic neurons, which can then co-align with developing blood vessels.

In addition to improving the odds that science will one day generate artificial organs from stem cells, this new insight has implications for rare inherited conditions such as neurofibro-matosis, tuberous sclerosis and Hirschsprung's disease.

"These observations may help explain certain human disease(s)... in which abnormalities of the nervous system appear to be associated with vascular abnormalities. We demonstrate here that modeling human development and disease in the lab must take into account multiple cell types in order to reflect the actual human condition.

"We can no longer rely on merely examining pure populations of one cell type or another."

Evan Snyder MD PhD, co-senior author, professor and director of the Center for Stem Cells and Regenerative Medicine at Sanford-Burnham.

(1) In the brain, pericytes help sustain the blood–brain barrier as well as several other homeostatic and hemostatic functions of the brain. These cells are also a key component of the neurovascular unit, which includes endothelial cells, astrocytes, and neurons. Pericytes regulate capillary blood flow, the clearance and phagocytosis of cellular debris, and the permeability of the blood–brain barrier. Pericytes stabilize and monitor the maturation of endothelial cells by means of direct communication between the cell membrane as well as through paracrine signaling.  A deficiency of pericytes in the central nervous system can cause the blood–brain barrier to break down. Wikipedia

Abstract
Highlights
•Neural crest (NC) cells drive neurovascular co-patterning, as modeled by hESC
•Autonomic differentiation of NC cells depends on contact with perivascular cells
•This requires endothelial-derived NO and T-cadherin-mediated interaction with VSMCs

Summary
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.

Co-authors include Lisette M. Acevedo, Jeffrey N. Lindquist, UC San Diego and Sanford-Burnham; Breda M. Walsh, Peik Sia, UC San Diego; Flavio Cimadamore, Connie Chen, Martin Denzel, Cameron D. Pernia, Barbara Ranscht, and Alexey Terskikh, Sanford-Burnham.

This research was funded, in part, by the National Institutes of Health (grants K01CA148897 and P20GM075059) and California Institute for Regenerative Medicine (grants CIRM-CL1-00511-1 and CIRM-RB3-02098).

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