Kenneth M Yamada

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Verified

Kenneth verified their affiliation via an institutional email.

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• MD, PhD
• NIH Distinguished Investigator and Chief, Cell Biology Section, NIDCR at National Institutes of Health

Integrins are key regulators of cell-matrix interactions during joint development and joint tissue homeostasis, as well as in the development of osteoarthritis (OA). The signalling cascades initiated by the interactions of integrins with a complex network of extracellular matrix (ECM) components and intracellular adaptor proteins orchestrate cellul...

Although mesenchyme is essential for inducing the epithelium of ectodermal organs, its precise role in organ-specific epithelial fate determination remains poorly understood. To elucidate the roles of tissue interactions in cellular differentiation, we performed single-cell RNA sequencing and imaging analyses on recombined tissues, where mesenchyme...

Mechanical cues sensed by integrins induce cells to produce proteases to remodel the extracellular matrix. Excessive protease production occurs in many degenerative diseases, including osteoarthritis, in which articular cartilage degradation is associated with the genesis of matrix protein fragments that can activate integrins. We investigated the...

A basic process in cancer is the breaching of basement-membrane barriers to permit tissue invasion. Cancer cells can use proteases and physical mechanisms to produce initial holes in basement membranes, but how cells squeeze through this barrier into matrix environments is not well understood. We used a 3D invasion model consisting of cancer-cell s...

Multicellular organisms generate tissues of diverse shapes and functions from cells and extracellular matrices. Their adhesion molecules mediate cell-cell and cell-matrix interactions, which not only play crucial roles in maintaining tissue integrity but also serve as key regulators of tissue morphogenesis. Cells constantly probe their environment...

Cancer invasion through basement membranes represents the initial step of tumor dissemination and metastasis. However, little is known about how human cancer cells breach basement membranes. Here, we used a three-dimensional in vitro invasion model consisting of cancer spheroids encapsulated by a basement membrane and embedded in 3D collagen gels t...

Cancer invasion through basement membranes represents the initial step of tumor dissemination and metastasis. However, little is known about how human cancer cells breach basement membranes. Here, we used a 3-dimensional in vitro invasion model consisting of cancer spheroids encapsulated by a basement membrane and embedded in 3D collagen gels to vi...

Article 3D mesenchymal cell migration is driven by anterior cellular contraction that generates an extracellular matrix prestrain Graphical abstract Highlights d A matrix prestrain propels fibroblasts and cancer cells through 3D environments d Anterior contractions sustain the matrix prestrain through enhanced cell protrusion d Both require high my...

Tissues consist of cells and their surrounding extracellular matrix (ECM). Cell–ECM interactions play crucial roles in embryonic development, differentiation, tissue remodeling, and diseases including fibrosis and cancer. Recent research advances in characterizing cell–matrix interactions include detailed descriptions of hundreds of ECM and associa...

Resistance to apoptosis due to caspase deregulation is considered one of the main hallmarks of cancer. However, the discovery of novel non-apoptotic caspase functions has revealed unknown intricacies about the interplay between these enzymes and tumor progression. To investigate this biological problem, we capitalized on a Drosophila tumor model wi...

Mammalian development demands precision. Millions of molecules must be properly located in temporal order, and their function regulated, to orchestrate important steps in cell cycle progression, apoptosis, migration and differentiation, to shape developing embryos. Ubiquitin and its associated enzymes act as cellular guardians to ensure precise spa...

The mechanisms underlying facial pain are still incompletely understood, posing major therapeutic challenges. Cyclin-dependent kinase 5 (Cdk5) is a key neuronal kinase involved in pain signaling. However, the regulatory roles of Cdk5 in facial pain signaling and the possibility of therapeutic intervention at the level of mouse trigeminal ganglion p...

Mammalian development demands precision. Millions of molecules must be properly located in temporal order, and their function regulated, to orchestrate important steps in cell cycle progression, apoptosis, migration and differentiation, to shape developing embryos. Ubiquitin and its associated enzymes act as cellular guardians to ensure precise spa...

The sites of interaction between a cell and its surrounding microenvironment serve as dynamic signaling hubs that regulate cellular adaptations during developmental processes, immune functions, wound healing, cell migration, cancer invasion and metastasis, as well as in many other disease states. For most cell types, these interactions are establis...

Mycoplasma hyorhinis (M. hyorhinis) lacks a cell wall and resists multiple antibiotics. We describe here the striking >90% inhibitory effect of hemin, a natural inducer of the cytoprotective enzyme heme oxygenase‐1 (HO‐1), on M. hyorhinis replication in chronically infected LNCaP prostate cancer cells. The role of HO‐1 in interrupting M. hyorhinis...

Many embryonic organs undergo epithelial morphogenesis to form tree-like hierarchical structures. However, it remains unclear what drives the budding and branching of stratified epithelia, such as in the embryonic salivary gland and pancreas. Here, we performed live-organ imaging of mouse embryonic salivary glands at single-cell resolution to revea...

The mechanisms underlying facial and oral pain are still incompletely understood, posing major therapeutic challenges. Cyclin-dependent kinase 5 (Cdk5) is a key neuronal kinase involved in pain signaling. However, the regulatory roles of Cdk5 in orofacial pain signaling and the possibility of therapeutic intervention at the level of mouse trigemina...

We describe a cellular contractile mechanism employed by fibroblasts and mesenchymal cancer cells to migrate in 3D collagen gels. During 3D spreading, fibroblasts strongly deform the matrix. They protrude, polarize, and initiate migration in the direction of highest extracellular matrix (ECM) deformation (prestrain). This prestrain is maintained th...

The vast majority of mammalian genomes are transcribed as non-coding RNA in what is referred to as "pervasive transcription." Recent studies have uncovered various families of non-coding RNA transcribed upstream of transcription start sites. In particular, highly unstable promoter upstream transcripts known as PROMPTs have been shown to be targeted...

Resistance to apoptosis due to caspase deregulation is considered one of the main hallmarks of cancer. However, the discovery of novel non-apoptotic caspase functions has revealed unknown intricacies about the interplay between these enzymes and tumor progression. To investigate this biological problem, we capitalized on a Drosophila tumor model hi...

During embryogenesis, many organs undergo branching morphogenesis to form tree-like hierarchical structures. However, it remains unclear what drives branching in stratified epithelia, such as in embryonic salivary gland and pancreas. Here, we performed live-organ imaging of mouse embryonic salivary glands at single-cell resolution to reveal branchi...

Background Three‐dimensional (3D) in vitro model systems can bridge the gap between regular two‐dimensional cell culture and whole‐animal studies. Analyses of cancer cell migration and invasion increasingly use differing 3D systems, which may produce conflicting findings. Aims We directly compared different 3D extracellular matrix systems for stud...

As the crucial non-cellular component of tissues, the extracellular matrix (ECM) provides both physical support and signaling regulation to cells. Some ECM molecules provide a fibrillar environment around cells, while others provide a sheet-like basement membrane scaffold beneath epithelial cells. In this Review, we focus on recent studies investig...

Description: Craniofacial region of a 13-day old mouse embryo by transmitted light microscopy. Categories: Research in NIH Labs and Clinics Type: Color, Photo Source: National Institute of Dental and Craniofacial Research (NIDCR) Creator: Craig Rhodes and Kenneth Yamada, LCDB, NIDCR Date Created: Unknown Date Added: 5/24/2012 Reuse Restrictions: No...

We have discovered that basement membrane and its major components can induce rapid, strikingly robust fibronectin organization. In this new matrix assembly mechanism, α5β1 integrin-based focal adhesions slide actively on the underlying matrix toward the ventral cell center through the dynamic shortening of myosin IIA-associated actin stress fibers...

Branching morphogenesis establishes the tree-like architecture of multiple organs during embryonic development. It requires coordinated, dynamic remodeling and signaling between tissues and the extracellular matrix (ECM). We review similarities and differences in the principles and mechanisms of three major examples of branching morphogenesis: lung...

Human pregnancy-specific glycoproteins (PSGs) serve immunomodulatory and pro-angiogenic functions during pregnancy and are mainly expressed by syncytiotrophoblast cells. While PSG mRNA expression in extravillous trophoblasts (EVTs) was reported, the proteins were not previously detected. By immunohistochemistry and immunoblotting, we show that PSGs...

Branching organs, including the salivary and mammary glands, lung, and kidney, arise as epithelial buds that are morphologically very similar. However, the mesenchyme is known to guide epithelial morphogenesis and to help govern cell fate and eventual organ specificity. We performed single-cell transcriptome analyses of 14,441 cells from embryonic...

Cell migration is essential for physiological processes as diverse as development, immune defence and wound healing. It is also a hallmark of cancer malignancy. Thousands of publications have elucidated detailed molecular and biophysical mechanisms of cultured cells migrating on flat, 2D substrates of glass and plastic. However, much less is known...

Fibronectin is a multifunctional, extracellular matrix glycoprotein that exists either as an insoluble multimeric fibrillar component of the extracellular matrix or as a soluble monomer. Cells attach to fibronectin through transmembrane integrin receptors and form a variety of cell-matrix contacts. Here we show that primary fibroblasts can use fibr...

This review describes how direct visualization of the dynamic interactions of cells with different extracellular matrix microenvironments can provide novel insights into complex biological processes. Recent studies have moved characterization of cell migration and invasion from classical 2D culture systems into 1D and 3D model systems, revealing mu...

We have discovered that basement membrane and its major components can induce rapid, strikingly robust fibronectin organization. In this new matrix assembly mechanism, α5β1 integrin-based focal adhesions slide actively on the underlying matrix towards the ventral cell center through the dynamic shortening of myosin IIA-associated actin stress fiber...

Durotaxis is a type of directed cell migration in which cells respond to a gradient of extracellular stiffness. Using automated tracking of positional data for large sample sizes of single migrating cells, we investigated 1) whether cancer cells can undergo durotaxis; 2) whether cell durotactic efficiency varies depending on the regional compliance...

The basement membrane is a thin but dense, sheet-like specialized type of extracellular matrix that has remarkably diverse functions tailored to individual tissues and organs. Tightly controlled spatial and temporal changes in its composition and structure contribute to the diversity of basement membrane functions. These different basement membrane...

Cell invasion across basement membrane barriers is important in both normal development and cancer metastasis. In this issue of Developmental Cell, Naegeli et al. (2017) identify a mechanism for breaching basement membranes. Localized lysosome exocytosis fuels generation of large, invasive cellular protrusions that expand tiny basement membrane ope...

Branching morphogenesis of developing organs requires coordinated but poorly understood changes in epithelial cell-cell adhesion and cell motility. We report that Btbd7 is a crucial regulator of branching morphogenesis in vivo. Btbd7 levels are elevated in peripheral cells of branching epithelial end buds, where it enhances cell motility and cell-c...

We identified primary human monocyte-derived macrophages (MDM) as vulnerable target cells for Zika virus (ZIKV) infection. We demonstrate dramatic effects of hemin, the natural inducer of the heme catabolic enzyme heme oxygenase-1 (HO-1), in the reduction of ZIKV replication in vitro. Both LLC-MK2 monkey kidney cells and primary MDM exhibited hemin...

Many embryonic organs undergo branching morphogenesis to maximize their functional epithelial surface area. Branching morphogenesis requires the coordinated interplay of multiple types of cells with the extracellular matrix (ECM). During branching morphogenesis, new branches form by “budding” or “clefting.” Cell migration, proliferation, rearrangem...

Primary human fibroblasts have the remarkable ability to use their nucleus like a piston, switching from low- to high-pressure protrusions in response to the surrounding three-dimensional (3D) matrix. Although migrating tumor cells can also change how they migrate in response to the 3D matrix, it is not clear if they can switch between high- and lo...

Cells migrate through 3D environments using a surprisingly wide variety of molecular mechanisms. These distinct modes of migration often rely on the same intracellular components, which are used in different ways to achieve cell motility. Recent work reveals that how a cell moves can be dictated by the relative amounts of cell-matrix adhesion and a...

Microbial biofilms and most eukaryotic tissues consist of cells embedded in a three-dimensional extracellular matrix. This matrix serves as a scaffold for cell adhesion and a dynamic milieu that provides varying chemical and physical signals to the cells. Besides a vast array of specific molecular components, an extracellular matrix can provide loc...

Cell dynamics is essential for development, tissue remodelling, and cancer progression. Traditionally, studies of cell dynamics have focused on the biochemical signals that control these processes; however, it has become evident that mechanical cues are also important in regulating cell dynamics. This issue provides an update of new and exciting de...

Cells engage in bidirectional communication with their surroundings. This reciprocal dialogue between cells and their cellular microenvironments often governs the maintenance and differentiation of stem/progenitor cells. Here, the authors present evidence that in developing salivary gland explants, a single posttranslational change in microtubules...

Anosmin is an extracellular matrix protein, and genetic defects in anosmin result in human Kallmann syndrome. It functions in neural crest formation, cell adhesion, and neuronal migration. Anosmin consists of multiple domains, and it has been reported to bind heparan sulfate, FGF receptor, and UPA. In this study, we establish cell adhesion/spreadin...

Durotaxis is a mechanism of directional migration in which cells respond to a stiffness gradient in their local microenvironment. While durotaxis has been characterized primarily in cells of mesenchymal origin, its role in cancer biology has not been clearly defined. At a cellular and molecular level, evidence suggests cancer cells sense and respon...

Cellular cytoskeletal systems play many pivotal roles in living organisms by controlling cell shape, division, and migration, which ultimately govern morphology, physiology, and functions of animals. Although the cytoskeletal systems are distinct and play different roles, there is growing evidence that these diverse cytoskeletal systems coordinate...

Promising drugs to treat Ebola virus (EBOV) infection are currently being developed, but so far none has shown efficacy in clinical trials. Drugs that can stimulate host innate defense responses may retard the progression of EBOV disease. We report here the dramatic effect of hemin, the natural inducer of the heme catabolic enzyme heme oxygenase-1...

Highly active antiretroviral therapy has significantly improved the life of HIV-1-infected individuals, yet complete eradication of HIV-1 reservoirs (i.e., latently infected cells) remains a major challenge. We have previously shown that induction of the endogenous cytoprotective enzyme heme oxygenase-1 (HO-1) by its natural substrate hemin reduces...

Cell migration is a multistep process that is intimately regulated by cell adhesion to govern a number of biological responses. Different mechanisms have been identified that regulate cell adhesions and cell migration, which has allowed categorization of cell adhesion into two broad groups. Furthermore, different modes of migration have been observ...

The physical properties of two-dimensional (2D) extracellular matrices (ECMs) modulate cell adhesion dynamics and motility, but little is known about the roles of local microenviron-mental differences in three-dimensional (3D) ECMs. Here we generate 3D collagen gels of varying matrix microarchitectures to characterize their regulation of 3D adhesio...

Timelapse movie of a HFF expressing EYFP-paxillin (green or white) migrating through 3D HR collagen (red). Right panel shows dual adhesion/ECM tracking (green/red vectors, respectively). Over the lifetime of the adhesion, there is relative lack of adhesion/ECM coupling as shown by the divergence of vectors as the adhesion retracts away from the ECM...

HFF expressing EYFP-paxillin (green or white) migrating through 3D FB16 collagen (red). Cell was treated with 25 μM blebbistatin and 1 μg ml-1 mAb13 to reduce β1 integrin binding. Inhibitors were added at the indicated time point. Protrusion initially occurs without cell body translocation. However, this is followed shortly by a release of the cell...

Structured illumination microscopy (SIM) illustrating the strikingly different architectures of homogeneous HR (top) and heterogeneous FB16 (bottom) Atto-488 labeled collagen gels 8-μm Z-stacks.

SIM rotational view of a 25-μm thick FB16 Atto-488 labeled collagen gel.

SIM rotational view of a 25-μm thick HR Atto-488 labeled collagen gel.

Timelapse movie of a HFF expressing EYFP-paxillin (green or white) migrating through 3D FB16 collagen (red). Right panel shows dual adhesion/ECM tracking (green/red vectors, respectively). Here in a highly stable adhesion, the relative adhesion/ECM coupling is high as demonstrated by the coinciding vector displacements. 30 seconds between frames. T...

HFF expressing EYFP-paxillin (green or white) migrating through 3D FB16 collagen (red). Cell was treated with 25 μM blebbistatin at the indicated time point. Note the increase in protrusion and reduced cell body translocation occurring after the relaxation of the ECM. Stage was moved during imaging, and then realigned to track cells over long time...

Timelapse movie of a fibroblast transfected with EGFP-Lifeact (green) demonstrates contact guidance-based protrusion along bundled collagen fibrils within a FB4 ECM (red). 30 seconds between frames. Total time 45 minutes.

Timelapse movie of a demonstrating of adhesion tracking within 3D FB4 collagen gels (red). EYFP-paxillin (green: 1st panel, white: panels 2-5) adhesions are shown with tracks (magenta) and vectors (green) that illustrate the local movements of cellular adhesions during 3D migration. 30 seconds between frames. Total time 33.5 minutes.

Supplementary Figures 1-8, Supplementary Discussion, Supplementary Methods and Supplementary References

Timelapse movie of a HFF expressing EYFP-paxillin (green or white) migrating through 3D HR collagen (red). Vectors (right panel) show the retrograde movement of adhesions. Red vectors illustrate adhesions that undergo rapid movement indicative of adhesion retraction. 30 seconds between frames. Total time 48.5 minutes.

The extracellular matrix (ECM) microenvironment plays a central role in cell migration by providing physiochemical information that influences overall cell behavior. Much of this external information is accessed by direct interaction of the cell with ECM ligands and structures via integrin-based adhesions that are hypothesized to act as mechanosens...

Primary human fibroblasts are remarkably adaptable, able to migrate in differing types of physiological 3D tissue and on rigid 2D tissue culture surfaces. The crawling behavior of these and other vertebrate cells has been studied intensively, which has helped generate the concept of the cell motility cycle as a comprehensive model of 2D cell migrat...

The normal skeletal developmental and homeostatic process termed osteoclastogenesis is exacerbated in numerous pathological conditions and causes excess bone loss. In cancer and HIV-1-infected patients, this disruption of homeostasis results in osteopenia and eventual osteoporesis. Counteracting the factors responsible for these metabolic disorders...

Growing concerns about the reproducibility of published research threaten to undermine the scientific enterprise and erode public trust. Conscientious application of "best practices" for the generation and reporting of research, along with post-publication access to raw data and other research materials, will protect the integrity of the research l...

Transfusion of blood and blood products contaminated with the pathogenic form of prion protein Prpsc, thought to be the causative agent of variant a Creutzfeldt–Jakob disease (vCJD), may result in serious consequences in recipients with a compromised immune system, for example, as seen in HIV-1 infection. In the present study, we demonstrate that t...

Cell interactions with the extracellular matrix (ECM) can regulate multiple cellular activities and the matrix itself in dynamic, bidirectional processes. One such process is local proteolytic modification of the ECM. Invadopodia of tumor cells are actin-rich proteolytic protrusions that locally degrade matrix molecules and mediate invasion. We rep...

Investigating cell migration in 3D settings has revealed that specific extracellular matrix environments require differential activities of the Rho GTPases for efficient migration. However, it is largely unknown how the activities of specific Rho GTPases are modulated to direct cell migration in response to different extracellular matrix cues. We h...

Small nuclear RNAs (snRNAs) are <200 nucleotide non-coding uridylate-rich RNAs. Although the functions of many snRNAs remain undetermined, a population of snRNAs is produced during the early phase of infection of cells by vaccinia virus. In the present study, we demonstrate a direct correlation between expression of the cytoprotective enzyme heme o...

Cells use actomyosin contractility to move through three-dimensional (3D) extracellular matrices. Contractility affects the type of protrusions cells use to migrate in 3D, but the mechanisms are unclear. In this work, we found that contractility generated high-pressure lobopodial protrusions in human cells migrating in a 3D matrix. In these cells,...

Rho-family GTPases govern distinct types of cell migration on different extracellular matrix proteins in tissue culture or three-dimensional (3D) matrices. We searched for mechanisms selectively regulating 3D cell migration in different matrix environments and discovered a form of Cdc42-RhoA crosstalk governing cell migration through a specific pai...

Many epithelial tissues expand rapidly during embryonic development while remaining surrounded by a basement membrane. Remodeling of the basement membrane is assumed to occur during branching morphogenesis to accommodate epithelial growth, but how such remodeling occurs is not yet clear. We report that the basement membrane is highly dynamic during...

Although much is known about how individual cytoskeletal systems contribute to physiological processes such as cell migration and branching morphogenesis, little is known about how these different systems actively coordinate their functions after polymerization. Here we show that both fibroblasts and developing glands reciprocally coordinate levels...

Background: Epithelial cells of developing embryonic organs, such as salivary glands, can display substantial motility during branching morphogenesis. Their dynamic movements and molecules involved in their migration are not fully characterized. Results: We generated transgenic mice expressing photo-convertible KikGR and tracked the movements of...

Embryonic mouse salivary gland undergoing branching morphogenesis stained for E-cadherin (blue) and collagen IV (red). From Region-Specific Epithelial Cell Dynamics During Branching Morphogenesis, Jeff C. Hsu, Hyun Koo, Jill S. Harunaga, Kazue Matsumoto, Andrew D. Doyle, and Kenneth M. Yamada, Developmental Dynamics 242:1066-1077.

The extracellular matrix (ECM) plays diverse regulatory roles throughout development. Coordinate interactions between cells within a tissue and the ECM result in the dynamic remodeling of ECM structure. Both chemical signals and physical forces that result from such microenvironmental remodeling regulate cell behavior that sculpts tissue structure....

We have elucidated a putative mechanism for the host resistance against HIV-1 infection of primary human monocyte-derived macrophages (MDM) stimulated with lipopolysaccharide (LPS). We show that LPS-activated MDM both inhibited HIV-1 entry into the cells and were refractory to post-entry productive viral replication. LPS-treated cells were virtuall...

Key roles for fibronectin and its integrin receptors have been postulated in the multiple cell-matrix interactions essential for chick embryo morphogenesis. However, mechanistic studies of these processes have been hampered by the current absence of sequence data and chicken cDNA clones for the major fibronectin receptor subunit, integrin α5 (ITGA5...

Branching morphogenesis is a crucial mechanism in embryonic development for establishing the architecture of many mammalian epithelial organs, including the salivary gland, lung, kidney, and mammary gland. It substantially expands the epithelial surface area available for secretion or absorption within many organs. Studies in three-dimensional ex v...

Cells migrating on flat two-dimensional (2D) surfaces use actin polymerization to extend the leading edge of the plasma membrane during lamellipodia-based migration. This mode of migration is not universal; it represents only one of several mechanisms of cell motility in three-dimensional (3D) environments. The distinct modes of 3D migration are st...

Xenotropic murine leukemia virus-related virus (XMRV) resembles endogenous murine leukemia virus and was used in this study as a model for a new retrovirus infecting human cells. We demonstrate that induction of an HO-1-mediated host cell response inhibited the susceptibility of LNCaP prostate cancer cells to XMRV infection and efficiently retarded...

The global prevalence of human immunodeficiency virus type-1 (HIV-1) and emerging infections with dengue, West Nile virus (WNV) and Leishmania donovani have increased greatly in recent decades, with rapidly growing numbers of people infected with these pathogens. Currently, no vaccine is available for the prevention of these infections, and no effe...

Introduction: Much like whole organisms, single cells have the ability to “sense” and respond to their surroundings. This “sensing” not only includes monitoring and responding to changes in extracellular chemical messages, but also the physical nature of the cell’s microenvironment, particularly the components of the extracellular matrix (ECM). Anc...