Peripheral sensory neurons promote angiogenesis in neurovascular models derived from hESCs

Kannan, Sathya; Lee, Marcus; Muthusamy, Senthilkumar; Blasiak, Agata; Sriram, Gopu; Cao, Tong

doi:10.1016/j.scr.2021.102231

Cited by 5 publications

(8 citation statements)

References 49 publications

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“…The influence of sensory neurons on endothelial cells has been attributed to CGRP and substance P secreted by sensory neurons which are shown to upregulate VEGFA, Type 4 collagen, Angiopoietin 1 and Matrix metalloproteinase 2 in endothelial cells [52]. ESCs-derived sensory neurons have been demonstrated to regulate angiogenesis in platforms incorporating ESCsderived endothelial cells [53]. Addition of CGRP has been shown to promote tube formation of HUVECs on Matrigel similar to VEGF supplementation [54].…”

Section: Discussionmentioning

confidence: 99%

Self-assembled innervated vasculature-on-a-chip to study nociception

et al. 2023

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Nociceptor sensory neurons play a key role in eliciting pain. An active crosstalk between nociceptor neurons and the vascular system at the molecular and cellular level is required to sense and respond to noxious stimuli. Besides nociception, interaction between nociceptor neurons and vasculature also contributes to neurogenesis and angiogenesis. In vitro models of innervated vasculature can greatly help delineate these roles while facilitating disease modeling and drug screening. Herein, we report the development of a microfluidic-assisted tissue model of nociception in the presence of microvasculature. The self-assembled innervated microvasculature was engineered using endothelial cells and primary dorsal root ganglion (DRG) neurons. The sensory neurons and the endothelial cells displayed distinct morphologies in presence of each other. The neurons exhibited an elevated response to capsaicin in the presence of vasculature. Concomitantly, increased transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor expression was observed in the DRG neurons in presence of vascularization. Finally, we demonstrated the applicability of this platform for modeling nociception associated with tissue acidosis. While not demonstrated here, this platform could also serve as a tool to study pain resulting from vascular disorders while also paving the way towards the development of innervated microphysiological models.

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Section: Discussionmentioning

confidence: 99%

Self-assembled innervated vasculature-on-a-chip to study nociception

et al. 2023

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“…With even more physiological relevance to the human system, the same researchers later used hiPSCs to successfully create similar self-assembled and fully stratified skin organoids including hair follicle formation ( Lee J. et al, 2020 , 2022 ; Ramovs et al, 2022 ). In another highly complementary organoid system, hESC-SNs were introduced to endothelial cells and proved essential for vascular formation ( Kannan et al, 2021 ). This again underlined the relevance of 3D tissue modeling for skin (disease) research.…”

Section: D and More Advanced Modelsmentioning

confidence: 99%

In vitro models for investigating itch

Mießner

Seidel²,

Smith³

2022

Front. Mol. Neurosci.

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Itch (pruritus) is a sensation that drives a desire to scratch, a behavior observed in many animals. Although generally short-lasting and not causing harm, there are several pathological conditions where chronic itch is a hallmark symptom and in which prolonged scratching can induce damage. Finding medications to counteract the sensation of chronic itch has proven difficult due to the molecular complexity that involves a multitude of triggers, receptors and signaling pathways between skin, immune and nerve cells. While much has been learned about pruritus from in vivo animal models, they have limitations that corroborate the necessity for a transition to more human disease-like models. Also, reducing animal use should be encouraged in research. However, conducting human in vivo experiments can also be ethically challenging. Thus, there is a clear need for surrogate models to be used in pre-clinical investigation of the mechanisms of itch. Most in vitro models used for itch research focus on the use of known pruritogens. For this, sensory neurons and different types of skin and/or immune cells are stimulated in 2D or 3D co-culture, and factors such as neurotransmitter or cytokine release can be measured. There are however limitations of such simplistic in vitro models. For example, not all naturally occurring cell types are present and there is also no connection to the itch-sensing organ, the central nervous system (CNS). Nevertheless, in vitro models offer a chance to investigate otherwise inaccessible specific cell–cell interactions and molecular pathways. In recent years, stem cell-based approaches and human primary cells have emerged as viable alternatives to standard cell lines or animal tissue. As in vitro models have increased in their complexity, further opportunities for more elaborated means of investigating itch have been developed. In this review, we introduce the latest concepts of itch and discuss the advantages and limitations of current in vitro models, which provide valuable contributions to pruritus research and might help to meet the unmet clinical need for more refined anti-pruritic substances.

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“…To establish proper connections within the vasculature and nervous system, chemotaxis of axons or blood vessels is orchestrated by similar structures: the growth cone in axons or tip cells in vessels. ,, Endothelial and nerve cells can both secrete angiogenic and neurogenic factors during vessels and nerve regeneration. Recent studies suggest that endothelial cell paracrine factors provide critical cues for recruiting and controlling innervation. , Specifically, endothelial cells secrete artemin and neurotrophin 3 that recruit axons to track alongside vessels. , In turn, nerves secrete VEGF in a spatiotemporally controlled manner to coordinate vessel growth . Further, stimulation of neuronal activity can also trigger angiogenesis. , …”

Section: Innervation and Angiogenesis In Craniofacial Tissue Regenera...mentioning

confidence: 99%

Tissue Engineered Neurovascularization Strategies for Craniofacial Tissue Regeneration

Fraser

Mereness

et al. 2021

ACS Appl. Bio Mater.

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Craniofacial tissue injuries, diseases, and defects, including those within bone, dental, and periodontal tissues and salivary glands, impact an estimated 1 billion patients globally. Craniofacial tissue dysfunction significantly reduces quality of life, and successful repair of damaged tissues remains a significant challenge. Blood vessels and nerves are colocalized within craniofacial tissues and act synergistically during tissue regeneration. Therefore, the success of craniofacial regenerative approaches is predicated on successful recruitment, regeneration, or integration of both vascularization and innervation. Tissue engineering strategies have been widely used to encourage vascularization and, more recently, to improve innervation through host tissue recruitment or prevascularization/innervation of engineered tissues. However, current scaffold designs and cell or growth factor delivery approaches often fail to synergistically coordinate both vascularization and innervation to orchestrate successful tissue regeneration. Additionally, tissue engineering approaches are typically investigated separately for vascularization and innervation. Since both tissues act in concert to improve craniofacial tissue regeneration outcomes, a revised approach for development of engineered materials is required. This review aims to provide an overview of neurovascularization in craniofacial tissues and strategies to target either process thus far. Finally, key design principles are described for engineering approaches that will support both vascularization and innervation for successful craniofacial tissue regeneration.

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Peripheral sensory neurons promote angiogenesis in neurovascular models derived from hESCs

Cited by 5 publications

References 49 publications

Self-assembled innervated vasculature-on-a-chip to study nociception

Self-assembled innervated vasculature-on-a-chip to study nociception

In vitro models for investigating itch

Tissue Engineered Neurovascularization Strategies for Craniofacial Tissue Regeneration

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