Author:
Isosaari Lotta,Vuorenpää Hanna,Yrjänäinen Alma,Kapucu Fikret Emre,Kelloniemi Minna,Pakarinen Toni-Karri,Miettinen Susanna,Narkilahti Susanna
Abstract
Abstract
Background
Neuronal networks receive and deliver information to regulate bodily functions while the vascular network provides oxygen, nutrients, and signaling molecules to tissues. Neurovascular interactions are vital for both tissue development and maintaining homeostasis in adulthood; these two network systems align and reciprocally communicate with one another. Although communication between network systems has been acknowledged, the lack of relevant in vitro models has hindered research at the mechanistic level. For example, the current used in vitro neurovascular models are typically established to be short-term (≤ 7 days) culture models, and they miss the supporting vascular mural cells.
Methods
In this study, we utilized human induced pluripotent stem cell (hiPSC) -derived neurons, fluorescence tagged human umbilical vein endothelial cells (HUVECs), and either human bone marrow or adipose stem/stromal cells (BMSCs or ASCs) as the mural cell types to create a novel 3D neurovascular network-on-a-chip model. Collagen 1–fibrin matrix was used to establish long-term (≥ 14 days) 3D cell culture in a perfusable microphysiological environment.
Results
Aprotinin-supplemented endothelial cell growth medium-2 (EGM-2) supported the simultaneous formation of neuronal networks, vascular structures, mural cell differentiation, and the stability of the 3D matrix. The formed neuronal and vascular networks were morphologically and functionally characterized. Neuronal networks supported vasculature formation based on direct cell contacts and by dramatically increasing the secretion of angiogenesis-related factors in multicultures in contrast to cocultures without neurons. Both utilized mural cell types supported the formation of neurovascular networks; however, the BMSCs seemed to boost neurovascular networks to greater extent.
Conclusions
Overall, our study provides a novel human neurovascular network model that is applicable for creating in vivo-like tissue models with intrinsic neurovascular interactions. The 3D neurovascular network model on chip forms an initial platform for the development of vascularized and innervated organ-on-chip and further body-on-chip concepts and offers the possibility for mechanistic studies on neurovascular communication both under healthy and in disease conditions.
Funder
Academy of Finland
State Research Financing of the Tampere University Hospital Specific Catchment Area
Doctoral Programme Funding at the Faculty of Medicine and Health Technology at Tampere University
Tampere University including Tampere University Hospital, Tampere University of Applied Sciences
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Molecular Biology,Biochemistry
Cited by
1 articles.
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1. Engineering Organ-on-a-Chip Systems for Vascular Diseases;Arteriosclerosis, Thrombosis, and Vascular Biology;2023-12