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12 Publications visible to you, out of a total of 12
Remodeling of self-assembled microvascular networks under long term flow.

Abstract (Expand)

The incorporation of a functional perfusable microvascular network (MVN) is a common requirement for most organ on-chip-models. Long-term perfusion of MVNs is often required for the maturation of organ … phenotypes and disease pathologies and to model the transport of cells and drugs entering organs. In our microphysiological system, we observe that flow can recover perfusion in regressed MVNs and maintain perfusable MVNs for at least 51 days. Throughout the 51 days, however, the MVNs are continuously remodeling to align with the direction of bulk flow and only appear to attain morphological homeostasis with the use of maintenance medium without growth factors. We observed that the flow resistance of the MVNs decreases over time, and using a computational model, we show that stable vessels have higher flow rates and velocities compared to regressing vessels. Cytokine analysis suggests that static conditions generate an inflammatory state, and that continuous flow reduces inflammation over an extended period. Finally, through bulk RNA sequencing we identify that both the endothelial and fibroblast cells are actively engaged in vascular and matrix remodeling due to flow and that these effects persist for at least 2 weeks. This MPS can be applied to study hemodynamically driven processes, such as metastatic dissemination or drug distribution, or to model long-term diseases previously not captured by MPS, such as chronic inflammation or aging-associated diseases.

Authors: M. Floryan, E. Cambria, A. Blazeski, M. F. Coughlin, Z. Wan, G. Offeddu, V. Vinayak, A. Kant, V. Shenoy, R. D. Kamm

Date Published: 18th Mar 2025

Publication Type: Journal

Wnt signaling modulates mechanotransduction in the epidermis to drive hair follicle regeneration.

Abstract (Expand)

Most wounds form scars without hair follicles. However, in the wound-induced hair neogenesis (WIHN) model of skin regeneration, wounds regenerate hair follicles if tissue rigidity is optimal. Although … WIHN depends on Wnt signaling, whether Wnt performs a mechanoregulatory role that contributes to regeneration remains uncharacterized. Here, we demonstrate that Wnt signaling affects mechanosensitivity at both cellular and tissue levels to drive WIHN. Atomic force microscopy revealed an attenuated substrate rigidity response in epidermal but not dermal cells of healing wounds. Super-resolution microscopy and nanoneedle probing of intracellular compartments in live human keratinocytes revealed that Wnt-induced chromatin remodeling triggers a 10-fold drop in nuclear rigidity without jeopardizing the nucleocytoskeletal mechanical coupling. Mechanistically, Wnt signaling orchestrated a massive reorganization of actin architecture and recruited adherens junctions to generate a mechanical syncytium-a cohesive contractile unit with superior capacity for force coordination and collective durotaxis. Collectively, our findings unveil Wnt signaling's mechanoregulatory role that manipulates the machinery of mechanotransduction to drive regeneration.

Authors: A. S. W. Oak, A. Bagchi, M. J. Brukman, J. Toth, J. Ford, Y. Zheng, A. Nace, R. Yang, J. C. Hsieh, J. E. Hayden, G. Ruthel, A. Ray, E. Kim, V. B. Shenoy, G. Cotsarelis

Date Published: 21st Feb 2025

Publication Type: Journal

Myofibroblasts reduce angiogenesis and vasculogenesis in a vascularized microphysiological model of lung fibrosis.

Abstract (Expand)

Lung fibrosis, characterized by chronic and progressive scarring, has no cure. Hallmarks are the accumulation of myofibroblasts and extracellular matrix, as well as vascular remodeling. The crosstalk … between myofibroblasts and vasculature is poorly understood, with conflicting reports on whether angiogenesis and vessel density are increased or decreased in lung fibrosis. We developed a microphysiological system that recapitulates the pathophysiology of lung fibrosis and disentangles myofibroblast-vascular interactions. Lung myofibroblasts maintained their phenotype in 3D without exogenous TGF-beta and displayed anti-angiogenic and anti-vasculogenic activities when cultured with endothelial cells in a microfluidic device. These effects, including decreased endothelial sprouting, altered vascular morphology, and increased vascular permeability, were mediated by increased TGF-beta1 and reduced VEGF secretion. Pharmacological interventions targeting these cytokines restored vascular morphology and permeability, demonstrating the potential of this model to screen anti-fibrotic drugs. This system provides insights into myofibroblast-vascular crosstalk in lung fibrosis and offers a platform for therapeutic development.

Authors: E. Cambria, A. Blazeski, E. C. Ko, T. Thai, S. Dantes, D. A. Barbie, S. E. Shelton, R. D. Kamm

Date Published: 14th Jan 2025

Publication Type: Journal

Chromatin conformation, gene transcription, and nucleosome remodeling as an emergent system.

Abstract (Expand)

In single cells, variably sized nanoscale chromatin structures are observed, but it is unknown whether these form a cohesive framework that regulates RNA transcription. Here, we demonstrate that the … human genome is an emergent, self-assembling, reinforcement learning system. Conformationally defined heterogeneous, nanoscopic packing domains form by the interplay of transcription, nucleosome remodeling, and loop extrusion. We show that packing domains are not topologically associated domains. Instead, packing domains exist across a structure-function life cycle that couples heterochromatin and transcription in situ, explaining how heterochromatin enzyme inhibition can produce a paradoxical decrease in transcription by destabilizing domain cores. Applied to development and aging, we show the pairing of heterochromatin and transcription at myogenic genes that could be disrupted by nuclear swelling. In sum, packing domains represent a foundation to explore the interactions of chromatin and transcription at the single-cell level in human health.

Authors: L. M. Almassalha, M. Carignano, E. P. Liwag, W. S. Li, R. Gong, N. Acosta, C. L. Dunton, P. C. Gonzalez, L. M. Carter, R. Kakkaramadam, M. Kroger, K. L. MacQuarrie, J. Frederick, I. C. Ye, P. Su, T. Kuo, K. I. Medina, J. A. Pritchard, A. Skol, R. Nap, M. Kanemaki, V. Dravid, I. Szleifer, V. Backman

Date Published: 10th Jan 2025

Publication Type: Journal

Confined cell migration along extracellular matrix space in vivo.

Abstract (Expand)

Collective migration of cancer cells is often interpreted using concepts derived from the physics of active matter, but the experimental evidence is mostly restricted to observations made in vitro. … Here, we study collective invasion of metastatic cancer cells injected into the mouse deep dermis using intravital multiphoton microscopy combined with a skin window technique and three-dimensional quantitative image analysis. We observe a multicellular but low-cohesive migration mode characterized by rotational patterns which self-organize into antiparallel persistent tracks with orientational nematic order. We analyze the deformations induced by the cells in the extracellular matrix and find broadly distributed strain bands with a prevalence of compression. A model of active nematic hydrodynamics is able to describe several statistical features of the experimentally observed flow, suggesting that collective cancer cell invasion can be interpreted as a nematic active fluid in the turbulent regime. Our results help elucidate the migration patterns of cancer cells in vivo and provide quantitative guidance for the development of realistic in vitro and in silico models for collective cell migration.

Authors: O. Chepizhko, J. M. Armengol-Collado, S. Alexander, E. Wagena, B. Weigelin, L. Giomi, P. Friedl, S. Zapperi, C. A. M. La Porta

Date Published: 7th Jan 2025

Publication Type: Journal

Personalized Vascularized Models of Breast Cancer Desmoplasia Reveal Biomechanical Determinants of Drug Delivery to the Tumor.

Abstract (Expand)

Desmoplasia in breast cancer leads to heterogeneity in physical properties of the tissue, resulting in disparities in drug delivery and treatment efficacy among patients, thus contributing to high … disease mortality. Personalized in vitro breast cancer models hold great promise for high-throughput testing of therapeutic strategies to normalize the aberrant microenvironment in a patient-specific manner. Here, tumoroids assembled from breast cancer cell lines (MCF7, SKBR3, and MDA-MB-468) and patient-derived breast tumor cells (TCs) cultured in microphysiological systems including perfusable microvasculature reproduce key aspects of stromal and vascular dysfunction causing impaired drug delivery. Models containing SKBR3 and MDA-MB-468 tumoroids show higher stromal hyaluronic acid (HA) deposition, vascular permeability, interstitial fluid pressure (IFP), and degradation of vascular HA relative to models containing MCF7 tumoroids or models without tumoroids. Interleukin 8 (IL8) secretion is found responsible for vascular dysfunction and loss of vascular HA. Interventions targeting IL8 or stromal HA normalize vascular permeability, perfusion, and IFP, and ultimately enhance drug delivery and TC death in response to perfusion with trastuzumab and cetuximab. Similar responses are observed in patient-derived models. These microphysiological systems can thus be personalized by using patient-derived cells and can be applied to discover new molecular therapies for the normalization of the tumor microenvironment.

Authors: G. S. Offeddu, E. Cambria, S. E. Shelton, K. Haase, Z. Wan, L. Possenti, H. T. Nguyen, M. R. Gillrie, D. Hickman, C. G. Knutson, R. D. Kamm

Date Published: 16th Oct 2024

Publication Type: Journal

Patient-specific vascularized tumor model: Blocking monocyte recruitment with multispecific antibodies targeting CCR2 and CSF-1R.

Abstract (Expand)

Tumor-associated inflammation drives cancer progression and therapy resistance, often linked to the infiltration of monocyte-derived tumor-associated macrophages (TAMs), which are associated with poor … prognosis in various cancers. To advance immunotherapies, testing on immunocompetent pre-clinical models of human tissue is crucial. We have developed an in vitro model of microvascular networks with tumor spheroids or patient tissues to assess monocyte trafficking into tumors and evaluate immunotherapies targeting the human tumor microenvironment. Our findings demonstrate that macrophages in vascularized breast and lung tumor models can enhance monocyte recruitment via CCL7 and CCL2, mediated by CSF-1R. Additionally, a multispecific antibody targeting CSF-1R, CCR2, and neutralizing TGF-beta (CSF1R/CCR2/TGF-beta Ab) repolarizes TAMs towards an anti-tumoral M1-like phenotype, reduces monocyte chemoattractant protein secretion, and blocks monocyte migration. This antibody also inhibits monocyte recruitment in patient-specific vascularized tumor models. In summary, this vascularized tumor model recapitulates the monocyte recruitment cascade, enabling functional testing of innovative therapeutic antibodies targeting TAMs in the tumor microenvironment.

Authors: H. T. Nguyen, E. L. Kan, M. Humayun, N. Gurvich, G. S. Offeddu, Z. Wan, M. F. Coughlin, D. C. Renteria, A. Loew, S. Wilson, C. Zhang, V. Vu, S. W. L. Lee, S. L. Tan, D. Barbie, J. Hsu, M. R. Gillrie, R. D. Kamm

Date Published: 3rd Sep 2024

Publication Type: Journal

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