The Pericytic Phenotype of Adipose Tissue‐Derived Stromal Cells Is Promoted by NOTCH2

Long‐term diabetes leads to macrovascular and microvascular complication. In diabetic retinopathy (DR), persistent hyperglycemia causes permanent loss of retinal pericytes and aberrant proliferation of microvascular endothelial cells (ECs). Adipose tissue‐derived stromal cells (ASCs) may serve to fu...

Full description

Saved in:
Bibliographic Details
Published in:Stem cells (Dayton, Ohio) Ohio), 2018-02, Vol.36 (2), p.240-251
Main Authors: Terlizzi, Vincenzo, Kolibabka, Matthias, Burgess, Janette Kay, Hammes, Hans Peter, Harmsen, Martin Conrad
Format: Article
Language:English
Subjects:
Aberration
Adipose stem cells
Adipose tissue
Angiogenesis
Cell proliferation
Cell surface
Conditioning
Diabetes
Diabetes mellitus
Diabetic retinopathy
Electroretinography
Endothelial cell
Endothelial cells
Eye (anatomy)
Growth factors
Hyperglycemia
Microvasculature
Networks
Notch
Notch protein
Notch2 protein
Paracrine signalling
Pericyte
Pericytes
Platelet-derived growth factor
Platelet-derived growth factor BB
Retina
Retinopathy
Stem cell transplantation
Stem cells
Stem cells microenvironment interaction
Stromal cells
Tube formation
Umbilical cord
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Long‐term diabetes leads to macrovascular and microvascular complication. In diabetic retinopathy (DR), persistent hyperglycemia causes permanent loss of retinal pericytes and aberrant proliferation of microvascular endothelial cells (ECs). Adipose tissue‐derived stromal cells (ASCs) may serve to functionally replace retinal pericytes and normalize retinal microvasculature during disease progression. We hypothesized that Notch signaling in ASC underlies regulation and stabilization of dysfunctional retinal microvascular networks such as in DR. ASC prominently and constitutively expressed NOTCH2. Genetic knockdown of NOTCH2 in ASC (SH‐NOTCH2) disturbed the formation of vascular networks of human umbilical cord vein endothelial cells both on monolayers of ASC and in organotypical three‐dimensional cocultures with ASC. On ASC SH‐NOTCH2, cell surface platelet‐derived growth factor receptor beta was downregulated which disrupted their migration toward the chemoattractant platelet‐derived growth factor beta subunits (PDGF‐BB) as well as to conditioned media from EC and bovine retinal EC. This chemoattractant is secreted by pro‐angiogenic EC in newly formed microvascular networks to attract pericytes. Intravitreal injected ASC SH‐NOTCH2 in oxygen‐induced retinopathy mouse eyes did not engraft in the preexisting retinal microvasculature. However, the in vivo pro‐angiogenic capacity of ASC SH‐NOTCH2 did not differ from controls. In this respect, multifocal electroretinography displayed similar b‐wave amplitudes in the avascular zones when either wild type ASC or SH‐NOTCH2 ASC were injected. In conclusion, our results indicate that NOTCH2 is essential to support in vitro vasculogenesis via juxtacrine interactions. In contrast, ongoing in vivo angiogenesis is influenced by paracrine signaling of ASC, irrespective of Notch signaling. Stem Cells 2018;36:240–251 NOTCH2 in adipose tissue‐derived stromal cells (ASCs) is essential for cell to cell communication. (a) Upon ASC NOTCH2 protein downregulation (ASC SH‐NOTCH2), PDGFRB expression was downregulated as well. ASC SH‐NOTCH2 were not able to migrate and acquire pericytic position in the mice retinal microvasculature. (b) Capillaries in the retina express a plethora of growth factors which are fundamental to attract cells of mesenchymal origin (ASC) to the site of injury. Platelet‐derived growth factor receptor beta on ASC promotes migration in response to endothelial secrete platelet‐derived growth factor beta subunits
ISSN:1066-5099
1549-4918
DOI:10.1002/stem.2726