hESC Differentiation toward an Autonomic Neuronal Cell Fate Depends on Distinct Cues from the Co-Patterning Vasculature

Lisette M Acevedo; Jeffrey N Lindquist; Breda M Walsh; Peik Sia; Flavio Cimadamore; Connie Chen; Martin Denzel; Cameron D Pernia; Barbara Ranscht; Alexey Terskikh; Evan Y Snyder; David A Cheresh

doi:10.1016/j.stemcr.2015.04.013

hESC Differentiation toward an Autonomic Neuronal Cell Fate Depends on Distinct Cues from the Co-Patterning Vasculature

Stem Cell Reports. 2015 Jun 9;4(6):1075-88. doi: 10.1016/j.stemcr.2015.04.013. Epub 2015 May 21.

Authors

Affiliations

¹ Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA; Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA; Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
² Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA; Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA.
³ Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA.
⁴ Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA.
⁵ Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
⁶ Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: [email protected].
⁷ Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: [email protected].

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood Vessels / physiology*
Cadherins / antagonists & inhibitors
Cadherins / genetics
Cadherins / metabolism
Cell Culture Techniques
Cell Differentiation
Cell Lineage
Cells, Cultured
Coculture Techniques
Ectoderm / cytology
Endothelium, Vascular / cytology
Endothelium, Vascular / metabolism
Human Embryonic Stem Cells / cytology*
Humans
Immunohistochemistry
Male
Mesoderm / cytology
Mice
Mice, Knockout
Models, Biological
Muscle, Smooth, Vascular / cytology
Muscle, Smooth, Vascular / metabolism
Neural Crest / cytology
Neural Crest / metabolism
Neurons / cytology
Neurons / metabolism*
Nitric Oxide / metabolism
Nitric Oxide Donors / metabolism
Nitric Oxide Synthase Type III / antagonists & inhibitors
Nitric Oxide Synthase Type III / genetics
Nitric Oxide Synthase Type III / metabolism
Peripherins / metabolism
RNA Interference
RNA, Small Interfering / metabolism
Tubulin / metabolism

Substances

Cadherins
H-cadherin
Nitric Oxide Donors
PRPH protein, human
Peripherins
RNA, Small Interfering
Tubulin
Nitric Oxide
Nitric Oxide Synthase Type III

Abstract

Publication types

MeSH terms

Substances

Grants and funding