A 3D tissue model-on-a-chip for studying the effects of human senescent fibroblasts on blood vessels

Pauty, Joris; Nakano, Shizuka; Usuba, Ryo; Nakajima, Tasuku; Johmura, Yoshikazu; Omori, Satotaka; Sakamoto, Naoya; Kikuchi, Akihiko; Nakanishi, Makoto; Matsunaga, Yukiko T.

doi:10.1039/d0bm01297a

Cited by 20 publications

(12 citation statements)

References 48 publications

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“…This vessel is embedded in the chip along with collagen-type-1 and senescent fibroblasts were applied to the chip for the observation of CS effect in the microchip environment. This study provided evidence on how to optimize senescent cell concentration in the experimental setup while enabling observing the role of CS ( Pauty et al, 2021 ).…”

Section: The Tools Of Cellular Senescence Researchmentioning

confidence: 97%

Translation of Cellular Senescence to Novel Therapeutics: Insights From Alternative Tools and Models

et al. 2022

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Increasing chronological age is the greatest risk factor for human diseases. Cellular senescence (CS), which is characterized by permanent cell-cycle arrest, has recently emerged as a fundamental mechanism in developing aging-related pathologies. During the aging process, senescent cell accumulation results in senescence-associated secretory phenotype (SASP) which plays an essential role in tissue dysfunction. Although discovered very recently, senotherapeutic drugs have been already involved in clinical studies. This review gives a summary of the molecular mechanisms of CS and its role particularly in the development of cardiovascular diseases (CVD) as the leading cause of death. In addition, it addresses alternative research tools including the nonhuman and human models as well as computational techniques for the discovery of novel therapies. Finally, senotherapeutic approaches that are mainly classified as senolytics and senomorphics are discussed.

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Section: The Tools Of Cellular Senescence Researchmentioning

confidence: 97%

Translation of Cellular Senescence to Novel Therapeutics: Insights From Alternative Tools and Models

et al. 2022

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“…[123] In addition to stiffness, other changes in nanomechanical properties have also been observed in senescent cells. Cellular traction force is known to increase with senescence, [131,132] with aged cells exhibiting increased stress disproportionality and localization of cellular traction stresses within the cells. [114] These have been found to be associated with increased mechanical maturity of adhesion points found in senescent cells.…”

Section: Biophysical Markersmentioning

confidence: 99%

“…For instance, Pauty et al had designed a 3D tissue model-on-a-chip that allows interaction between fibroblasts and the ECM to study the effects of human senescent fibroblasts on blood vessels. [131] Microfluidics are also a useful tool for studying drug delivery techniques. [169][170][171][172] However, depending on the end use and complexity of study involved, senescent ECM may need to be modeled to design a microfluidic platform with high fidelity and physiological or pathological relevance.…”

Section: In Vitro Modelsmentioning

confidence: 99%

Targeted Therapeutics Delivery by Exploiting Biophysical Properties of Senescent Cells

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Chan

Tay

2021

Adv Funct Materials

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Cellular senescence refers to a state of irreversible arrest of cell proliferation in response to various forms of cellular stress. It is known that the accumulation of senescent cells is a hallmark of aging, and mounting evidence has shown that the chronic accumulation of senescent cells is a significant contributor to various deleterious age-related pathologies. To limit the detrimental impacts of cellular senescence, there has been growing interest in targeted delivery of therapeutics to senescent cells to treat age-related pathologies and promote healthy aging. Two popular strategies include the elimination of senescent cells using senolytic drugs, and rejuvenation of senescent cells. To that end, it is integral that the delivery of senolytics, senomorphics or rejuvenating biomolecules to senescent cells are highly selective to enhance delivery efficacy and safety. However, there is little understanding of how senescence-associated biophysical changes such as cellular size and stiffness can be exploited for targeted therapeutics delivery. In this review, the biomolecular and biophysical markers of senescence along with senescence models and emerging therapeutics are first described. This review then focuses on how biophysical properties can be exploited for targeted therapeutics delivery, using approaches like nanoparticles, electroporation, sonoporation, photoporation and high aspect-ratio nanostructures to senescent cells.

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“…To prepare a 3D microvessel with CapSCs in its collagen gel microenvironment, the polydimethylsiloxane (PDMS)-based chips (25 mm × 25 mm × 5 mm: width × length × height) were used as previously described [ 35 ]. To prevent the detachment of the collagen gel from the PDMS surface during cell culture, the surface modification was performed as follows.…”

Section: Methodsmentioning

confidence: 99%

Image-based crosstalk analysis of cell–cell interactions during sprouting angiogenesis using blood-vessel-on-a-chip

et al. 2022

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Background Sprouting angiogenesis is an important mechanism for morphogenetic phenomena, including organ development, wound healing, and tissue regeneration. In regenerative medicine, therapeutic angiogenesis is a clinical solution for recovery from ischemic diseases. Mesenchymal stem cells (MSCs) have been clinically used given their pro-angiogenic effects. MSCs are reported to promote angiogenesis by differentiating into pericytes or other vascular cells or through cell–cell communication using multiple protein–protein interactions. However, how MSCs physically contact and move around ECs to keep the sprouting angiogenesis active remains unknown. Methods We proposed a novel framework of EC–MSC crosstalk analysis using human umbilical vein endothelial cells (HUVECs) and MSCs obtained from mice subcutaneous adipose tissue on a 3D in vitro model, microvessel-on-a-chip, which allows cell-to-tissue level study. The microvessels were fabricated and cultured for 10 days in a collagen matrix where MSCs were embedded. Results Immunofluorescence imaging using a confocal laser microscope showed that MSCs smoothed the surface of the microvessel and elongated the angiogenic sprouts by binding to the microvessel’s specific microstructures. Additionally, three-dimensional modeling of HUVEC–MSC intersections revealed that MSCs were selectively located around protrusions or roots of angiogenic sprouts, whose surface curvature was excessively low or high, respectively. Conclusions The combination of our microvessel-on-a-chip system for 3D co-culture and image-based crosstalk analysis demonstrated that MSCs are selectively localized to concave–convex surfaces on scaffold structures and that they are responsible for the activation and stabilization of capillary vessels.

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A 3D tissue model-on-a-chip for studying the effects of human senescent fibroblasts on blood vessels

Abstract: Senescent cells modify their environment and cause tissue aging that leads to organ dysfunction. Developing strategies for healthy aging rises a need for in vitro models that enables to study senescence and senotherapeutics at a tissue level.

Cited by 20 publications

References 48 publications

Translation of Cellular Senescence to Novel Therapeutics: Insights From Alternative Tools and Models

Translation of Cellular Senescence to Novel Therapeutics: Insights From Alternative Tools and Models

Targeted Therapeutics Delivery by Exploiting Biophysical Properties of Senescent Cells

Image-based crosstalk analysis of cell–cell interactions during sprouting angiogenesis using blood-vessel-on-a-chip

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