Stromal cell identity modulates vascular morphogenesis in a microvasculature-on-a-chip platform

Margolis, Emily A.; Cleveland, D E; Kong, Ying; Beamish, Jeffrey A.; Wang, William Y.; Baker, Brendon M.; Putnam, Andrew J.

doi:10.1039/d0lc01092h

Cited by 23 publications

(22 citation statements)

References 53 publications

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“…Perivascular cells are essential for proper maturation and stabilization of the forming vascular networks ( Bergers and Song, 2005 ; Sweeney and Foldes, 2018 ). Previous studies investigating 3D vasculature formation have emphasized that network phenotype and maturation strongly depend on the used perivascular cell type ( Grainger and Putnam, 2011 ; Jeon et al, 2014 ; Kniebs et al, 2020 ; Rambøl et al, 2020 ; Margolis et al, 2021 ). While various cell types have been reported to support vasculature formation in microfluidic devices ( Kim et al, 2013 ; Li et al, 2017 ; Campisi et al, 2018 ; Zeinali et al, 2018 ; Rambøl et al, 2020 ), differences in experimental set-up complicate the direct comparison of the results obtained with different vasculature-supporting cells.…”

Section: Discussionmentioning

confidence: 99%

Vasculogenic Potency of Bone Marrow- and Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells Results in Differing Vascular Network Phenotypes in a Microfluidic Chip

Mykuliak

Yrjänäinen

Mäki

et al. 2022

Front. Bioeng. Biotechnol.

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The vasculature is an essential, physiological element in virtually all human tissues. Formation of perfusable vasculature is therefore crucial for reliable tissue modeling. Three-dimensional vascular networks can be formed through the co-culture of endothelial cells (ECs) with stromal cells embedded in hydrogel. Mesenchymal stem/stromal cells (MSCs) derived from bone marrow (BMSCs) and adipose tissue (ASCs) are an attractive choice as stromal cells due to their natural perivascular localization and ability to support formation of mature and stable microvessels in vitro. So far, BMSCs and ASCs have been compared as vasculature-supporting cells in static cultures. In this study, BMSCs and ASCs were co-cultured with endothelial cells in a fibrin hydrogel in a perfusable microfluidic chip. We demonstrated that using MSCs of different origin resulted in vascular networks with distinct phenotypes. Both types of MSCs supported formation of mature and interconnected microvascular networks-on-a-chip. However, BMSCs induced formation of fully perfusable microvasculature with larger vessel area and length whereas ASCs resulted in partially perfusable microvascular networks. Immunostainings revealed that BMSCs outperformed ASCs in pericytic characteristics. Moreover, co-culture with BMSCs resulted in significantly higher expression levels of endothelial and pericyte-specific genes, as well as genes involved in vasculature maturation. Overall, our study provides valuable knowledge on the properties of MSCs as vasculature-supporting cells and highlights the importance of choosing the application-specific stromal cell source for vascularized organotypic models.

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Section: Discussionmentioning

confidence: 99%

Vasculogenic Potency of Bone Marrow- and Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells Results in Differing Vascular Network Phenotypes in a Microfluidic Chip

Mykuliak

Yrjänäinen

Mäki

et al. 2022

Front. Bioeng. Biotechnol.

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“…[138] The pericytes improved the barrier function of ECs and led to an immune response that is physiologically relevant. Besides, the 3D approach allows studying assembly-involved angiogenesis, [133,[141][142][143][144][145] vessel-matrix interactions in terms of matrix stiffness [146] and niche effects, [147] antiangiogenetic therapeutic drugs, [148] morphogenesis, [149] cellular interactions, [150] mass transport, [151] and tissue regeneration. [152] Capillary vessels are small in diameter yet make up the major volume of the circulation system and play central roles in mass transport and cell infiltration.…”

Section: On-chip Recapitulationmentioning

confidence: 99%

Building Blood Vessel Chips with Enhanced Physiological Relevance

Gerhard‐Herman

Zhang

2023

Adv Materials Technologies

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Due to the bioengineering nature, tissue chips allow the manipulation of cellular composition [11] and a range of biophysical and biochemical environmental cues, including but not limited to cell-ECM interactions, dynamic flows, chemical species gradients, substrate stiffness, [12] and active mechanical stimuli. [13,14] In particular, the on-chip adoption of patients' cells, either primary or induced human pluripotent stem cells (hiPSCs), makes a bespoke and patient-specific tissue model in line with the goal of precision medicine. [15] In contrast, small animal-based models exhibit notable genetic and cellular differences from human physiology, which may lead to biased results regarding disease pathogenesis and therapeutic effects. [16,17] Furthermore, tissue chips can precisely control and decouple multiple experimental factors, beneficial for exploiting the inherently complex human physiology, in contrast to other in vitro models, such as Petri dish-based ones, which are focused on maintaining cell proliferation in vitro. Thus, tissue chips, as a viable alternative to other tissue/disease-modeling approaches, are promising for in vitro recapitulation of the sophisticated human physiology and pathology at the tissue and organ level and are expected to transform the landscapes of fundamental biological research, [18][19][20] drug screening and toxicology, [21][22][23][24] and possibly, clinical trials. [25,26] Tissue chips can construct a broad range of tissue-and organ-analogs in vitro, including the vessel and vascular networks, [27][28][29] muscles, [30][31][32][33] liver, [34][35][36] lung, [37][38][39] brain, [40,41] kidney, [42][43][44][45][46] gut, [47,48] bone marrow, [49] corneal, [50,51] tumor, [52][53][54][55][56] as well as the integrated multiple tissues/organs, [57][58][59] such as liver-kidney, [60][61][62] neuromuscular junction, [63] and a recirculating system with up to 13 organs. [64] Of note, these tissue chips may rely on the same set of technical approaches yet recapitulate the specific tissue (patho)physiology by considering tissue-specific cellular and matrix composition.Among all tissues/organs modeled in the chips, the blood vessel is of particular interest, largely for the following reasons (Figure 1). [65,66] i) The blood vessel exists in all tissues/ organs throughout the body up to the epithelial layer covering surfaces. Thus, the on-chip reconstruction of the vessel or its analog is often a prerequisite for constructing a tissue analog.ii) The blood vessel is both the structural basis of circulating blood flow throughout the body and responsible for many Blood vessel chips are bioengineered microdevices, consisting of biomaterials, human cells, and microstructures, which recapitulate essential vascular structure and physiology and allow a well-controlled microenvironment and spatial-temporal readouts. Blood vessel chips afford promising opportunities to understand molecular and cellular mechanisms underlying a range of vascular diseases. The physiological relevance is key to these ...

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“…Other than pro-angiogenic factors, stromal cells also play a vital role in vasculogenesis [ 4 , 45 , 46 ]. In order to investigate the interplays between interstitial flow and fibroblasts, and their combined effects on vasculogenesis, we first explored the possibility of constructing perfusable vasculatures without NHLFs and studied the effect of interstitial flow on that NHLFs-free vasculogenic process.…”

Section: Resultsmentioning

confidence: 99%

“…The disparity between those works and this finding here should be attributed to the absence of stromal cells. Stromal cells have the capacity to wrap around blood vessels, deposit basement membrane, and stabilize the vessels [ 46 ]. In the absence of the NHLFs, vessels tended to regress rapidly under static conditions, even with the secretions of NHLFs.…”

Section: Resultsmentioning

confidence: 99%

A Transwell-Based Vascularized Model to Investigate the Effect of Interstitial Flow on Vasculogenesis

et al. 2022

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Interstitial flow plays a significant role in vascular system development, mainly including angiogenesis and vasculogenesis. However, compared to angiogenesis, the effect of interstitial flow on vasculogenesis is less explored. Current in vitro models for investigating the effect of interstitial flow on vasculogenesis heavily rely on microfluidic chips, which require microfluidic expertise and facilities, and may not be accessible to biological labs. Here, we proposed a facile approach to building perfusable vascular networks through the self-assembly of endothelial cells in a modified transwell format and investigated the effect of interstitial flow on vasculogenesis. We found that the effect of interstitial flow on vasculogenesis was closely related to the existence of VEGF and fibroblasts in the developed model: (1) In the presence of fibroblasts, interstitial flow (within the range of 0.1–0.6 μm/s) facilitated the perfusability of the engineered vasculatures. Additional VEGF in the culture medium further worked synergically with interstitial flow to develop longer, wider, denser, and more perfusable vasculatures than static counterparts; (2) In the absence of fibroblasts, vasculatures underwent severe regression within 7 days under static conditions. However, interstitial flow greatly inhibited vessel regression and enhanced vascular perfusability and morphogenesis without the need for additional VEGF. These results revealed that the effect of interstitial flow might vary depending on the existence of VEGF and fibroblasts, and would provide some guidelines for constructing in vitro self-assembled vasculatures. The established transwell-based vascularized model provides a simple method to build perfusable vasculatures and could also be utilized for creating functional tissues in regenerative medicine.

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Stromal cell identity modulates vascular morphogenesis in a microvasculature-on-a-chip platform

Abstract: We employed a multiplexed microvasculature-on-a-chip platform to investigate the impact of stromal cell identity on microvascular network formation and perfusion.

Cited by 23 publications

References 53 publications

Vasculogenic Potency of Bone Marrow- and Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells Results in Differing Vascular Network Phenotypes in a Microfluidic Chip

Vasculogenic Potency of Bone Marrow- and Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells Results in Differing Vascular Network Phenotypes in a Microfluidic Chip

Building Blood Vessel Chips with Enhanced Physiological Relevance

A Transwell-Based Vascularized Model to Investigate the Effect of Interstitial Flow on Vasculogenesis

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