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At least 145 records · Page 8Linked to original sources
PubMed2005

Galactose-carrying polymers as extracellular matrices for liver tissue engineering.

Extracellular matrix (ECM) plays important roles in tissue engineering because cellular growth and differentiation, in the two-dimensional cell culture as well as in the three-dimensional space of the developing organism, require ECM with which the cells can interact. Especially, the bioartificial liver-assist device or regeneration of the liver-tissue substitutes for liver tissue engineering requires a suitable ECM for hepatocyte culture because hepatocytes are anchorage-dependent cells and are highly sensitive to the ECM milieu for the maintenance of their viability and differentiated functions. Galactose-carrying synthetic ECMs derived from synthetic polymers and natural polymers bind hepatocytes through a receptor-mediated mechanism, resulting in enhanced hepatocyte functions. Attachment and functions of hepatocytes were affected by physico-chemical properties including ECM geometry as well as the type, density and orientation of galactose. Also, cellular environment, medium composition and dynamic culture system influenced liver-specific functions of hepatocytes beside ECM.

Animals↗
PubMed2005

Artificial cell-cell communication in yeast Saccharomyces cerevisiae using signaling elements from Arabidopsis thaliana.

The construction of synthetic cell-cell communication networks can improve our quantitative understanding of naturally occurring signaling pathways and enhance our capabilities to engineer coordinated cellular behavior in cell populations. Towards accomplishing these goals in eukaryotes, we developed and analyzed two artificial cell-cell communication systems in yeast. We integrated Arabidopsis thaliana signal synthesis and receptor components with yeast endogenous protein phosphorylation elements and new response promoters. In the first system, engineered yeast 'sender' cells synthesize the plant hormone cytokinin, which diffuses into the environment and activates a hybrid exogenous/endogenous phosphorylation signaling pathway in nearby engineered yeast 'receiver' cells. For the second system, the sender network was integrated into the receivers under positive-feedback regulation, resulting in population density-dependent gene expression (that is, quorum sensing). The combined experimental work and mathematical modeling of the systems presented here can benefit various biotechnology applications for yeast and higher level eukaryotes, including fermentation processes, biomaterial fabrication and tissue engineering.

Alkyl and Aryl Transferases↗
PubMed2000

Superior tumor protection induced by a cellular vaccine carrying a tumor-specific T helper epitope by genetic exchange of the class II-associated invariant chain peptide.

Efficient loading of MHC class II molecules with a T helper epitope of choice can be achieved through genetic exchange of the MHC class II-associated invariant chain peptide (CLIP) sequence with a sequence encoding the helper peptide. We have now used this method to engineer a cellular vaccine that continuously expresses a tumor-specific helper epitope in a defined costimulatory context. We provide evidence (a) that this cellular vaccine induces peptide-specific helper T cells in vivo that are functional in protecting mice from challenge with a highly aggressive tumor, (b) that this vaccine can directly prime tumor-specific helper T cells in vivo, and (c) that this cellular vaccine is superior compared with similar cells loaded with synthetic T helper peptide in inducing tumor protection. In conclusion, cellular vaccines for activation of antigen-specific helper T cells can be greatly improved by the introduction of invariant chain constructs containing a T helper epitope by class II-associated invariant chain peptide exchange.

Amino Acid Sequence↗
PubMedDate not supplied

Functional genomic technologies: creating new paradigms for fundamental and applied biology.

New technologies that analyze the behavior of thousands of genes in parallel are creating, for the first time, a foundation of data for building integrated models of cellular processes. This review discusses the general issues of utilizing genomic methods in fundamental and applied research settings, using the study of stress responses and improvement of secondary metabolite production as examples. A fusion of concepts from biological and nonbiological disciplines, including mathematics, computer science, physics, chemistry, and engineering, is required to address the theoretical and experimental challenges facing the field of genomics, and together promise great breakthroughs in our understanding and engineering of cellular systems.

Biotechnology↗
PubMed1996

Evolution of bone transplantation: molecular, cellular and tissue strategies to engineer human bone.

Bone defects occur in a wide variety of clinical situations, and their reconstruction to provide mechanical integrity to the skeleton is a necessary step in the patient's rehabilitation. The current gold standard for bone reconstruction, the autogenous bone graft, works well in many circumstances. However, autograft reconstruction, along with the available alternatives of allogenous bone graft or poly(methylmethacrylate) bone cement, do not solve all instances of bone deficiency. Novel materials, cellular transplantation and bioactive molecule delivery are being explored alone and in various combinations to address the problem of bone deficiency. The goal of these strategies is to exploit the body's natural ability to repair injured bone with new bone tissue, and to then remodel that new bone in response to the local stresses it experiences. In general, the strategies discussed in this paper attempt to provide the reconstructed region with appropriate initial mechanical properties, encourage new bone to form in the region, and then gradually degrade to allow the new bone to remodel and assume the mechanical support function. Several of the concepts presented below are already finding clinical applications in early patient trials.

Biocompatible Materials↗
PubMed2004

Controlling the cellular organization of tissue-engineered cardiac constructs.

There are currently no effective treatments to restore the cardiac muscle lost because of ischemia for the millions of people who suffer heart attacks annually. Cell therapy procedures have emerged as novel therapeutic strategies for treatment of heart failure after myocardial infarction but have been hampered by the lack of adequate cell sources of cardiomyocytes and by the inability to integrate cell grafts into cardiac muscle. A cardiac patch composed of organized and functional cardiomyocytes could drastically enhance the efficacy of this important clinical approach. Here, we report our ongoing efforts to develop a bioartificial cardiac muscle capable of synchronized multidirectional contraction within a three-dimensional hydrogel scaffold. Neonatal rat cardiomyocytes, smooth muscle cells, and reconstituted polymeric collagen enriched with growth factors and hormones are used. A bioreactor system is used to impart precise strains onto the developing tissue constructs in vitro. The results demonstrate that cell-mediated collagen compaction is significantly enhanced by strain preconditioning, resulting in a more favorable cellular organization. Furthermore, the results demonstrate that strain stimulation guides cellular orientation in the direction of applied strain (i.e., in the circumferential direction). Hence, we demonstrate the importance of mechanical preconditioning as a means of promoting the in vitro development of engineered cardiac muscle for use with myocardial regeneration therapies.

Animals↗
PubMed1995

Enzymes, artificial cells and the nature of biological information.

Recent progresses in enzyme processing within an expanding array of disciplines make the informational analysis of the whole enzymic complexity of the simplest cellular systems appear as a plausible interdisciplinary enterprise. The term 'artificial cell' could be used as a label to encompass these global information processing models of the cell. In a simplified view, three different degrees of enzymic complexity emerge: self-organization, self-reshaping and self-modification. They imply that metabolic enzyme networks endowed with a signaling system and with a 'DNA world', constitute a genuine information processing engine for cellular problem solving, a true molecular 'society'. Philosophically, a new path can be followed to discuss the biological foundations and the paradoxes of the information concept. Other 'informational societies' could be analyzed in a similar way.

Animals↗
PubMed2006

Protein and cell micropatterning and its integration with micro/nanoparticles assembly.

Micropatterning of proteins and cells has become very popular over the past decade due to its importance in the development of biosensors, microarrays, tissue engineering and cellular studies. This article reviews the techniques developed for protein and cell micropatterning and its biomedical applications. The prospect of integrating micro and nanoparticles with protein and cell micropatterning is discussed. The micro/nanoparticles are assembled into patterns and form the substrate for proteins and cell attachment. The assembled particles create a micro or nanotopography, depending on the size of the particles employed. The nonplanar structure can increase the surface area for biomolecules attachment and therefore enhance the sensitivity for detection in biosensors. Furthermore, a nanostructured substrate can influence the conformation and functionality of protein attached to it, while cellular response in terms of morphology, adhesion, proliferation, differentiation, etc. can be affected by a surface expressing micro or nanoscale structures. Proteins and cells tend to lose their normal functions upon attachment to substrate. By recognizing the types of topography that are favourable for preserving proteins and cell behaviour, and integrating it with micropattering will lead to the development of functional protein and cell patterns.

Biocompatible Materials↗
PubMed2000

Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep.

Mesenchymal stem cells are multipotent cells that can be isolated from adult bone marrow and can be induced in vitro and in vivo to differentiate into a variety of mesenchymal tissues, including bone, cartilage, tendon, fat, bone marrow stroma, and muscle. Despite their potential clinical utility for cellular and gene therapy, the fate of mesenchymal stem cells after systemic administration is mostly unknown. To address this, we transplanted a well-characterized human mesenchymal stem cell population into fetal sheep early in gestation, before and after the expected development of immunologic competence. In this xenogeneic system, human mesenchymal stem cells engrafted and persisted in multiple tissues for as long as 13 months after transplantation. Transplanted human cells underwent site-specific differentiation into chondrocytes, adipocytes, myocytes and cardiomyocytes, bone marrow stromal cells and thymic stroma. Unexpectedly, there was long-term engraftment even when cells were transplanted after the expected development of immunocompetence. Thus, mesenchymal stem cells maintain their multipotential capacity after transplantation, and seem to have unique immunologic characteristics that allow persistence in a xenogeneic environment. Our data support the possibility of the transplantability of mesenchymal stem cells and their potential utility in tissue engineering, and cellular and gene therapy applications.

Adipocytes↗
PubMed2005

Nanostructured designs of biomedical materials: applications of cell sheet engineering to functional regenerative tissues and organs.

Biomaterials surface design is critical for control of cell-materials interactions. Materials surface characteristics important to cell-materials interactions are the following: (a) nonfouling surfaces where cells cannot interact; (b) surfaces that interact with cells but do not alter cell morphology or metabolism (passive adhesion processes); and (c) surfaces that strongly interact with cells and cell-surface receptors to alter cell shape after metabolic interactions (active adhesion). In this paper, we briefly discuss the relationship between materials surface characteristics and cells for biomaterials designs in these categories. We have extensively investigated the thermoresponsive polymer, poly(N-isopropylacrylamide) (PIPAAm), as grafted surfaces allowing recovery of confluent cell monolayers as contiguous living cell sheets for tissue engineering applications. Cellular interactions with PIPAAm-grafted surfaces can be regulated vertically using the thickness of the PIPAAm-grafted layers in nanometer-scale levels, as well as laterally (spatially) using nano-patterned PIPAAm chemistry on various other surface chemistries. PIPAAm-grafted surfaces with 15-20-nm thick layers exhibit temperature-dependent cell adhesion/detachment control, while surfaces with PIPAAm layer thicknesses of more than 30 nm do not support cell adhesion. These changes in cell adhesion are explained by the limited mobility of the surface grafted polymer chains as a function of grafting, hydration, and temperature.

Animals↗
PubMed2000

A cell surface-displayed anti-c-myc single-chain antibody: new perspectives for the genetic improvement of cellular tumor vaccines.

We have shown recently that cell surface-bound, single-chain Fv antibodies (scFv) are a powerful tool for the improvement of cellular tumor vaccines. To simplify this approach and to develop a general tool for the generation and improvement of cellular tumor vaccines, we chose an scFv against a peptide from the human proto-oncogene c-myc that could anchor any c-myc-tagged protein to the cell surface. The retroviral vector p50-Mx-neo (pMESV) was used to express scFv on the surface of the human melanoma line SkMel63. The cell-bound anti-c-myc scFv bound specifically to a soluble purified anti-CD28 scFv carrying a c-myc peptide-tag at its C terminus. Proof of principle was determined by incubating human peripheral blood lymphocytes with a mixture of (a) anti-c-myc-transfected SkMel63 cells binding the anti-CD28 scFv and (b) SkMel63 cells transfected with an anti-CD3 scFv. A clear synergistic effect on T-cell activation was observed that was comparable with that obtained in previous studies using SkMel63 cells transfected with the gene for the anti-CD28 scFv. As the cell surface-displayed anti-c-myc scFv can bind any c-myc-tagged protein of interest, this technique facilitates the genetic engineering of cellular vaccines for the therapy of virtually all human neoplasias.

Antibodies, Monoclonal↗
PubMed1994

Ligand-induced adhesion to activated endothelium and to vascular cell adhesion molecule-1 in lymphocytes transfected with the N-formyl peptide receptor.

Binding of FMLP to the neutrophil N-formyl peptide receptor (FPR) transmits signals through pertussis toxin-sensitive G proteins triggering Ca2+ flux, superoxide production, granule exocytosis, and neutrophil aggregation and adhesion involving the beta 2 (CD18) integrins. Expression of the FPR in mouse fibroblasts or human kidney cells has been shown to confer an N-formyl peptide-inducible Ca2+ flux in transfectants. Here we demonstrate that the transfected receptor can also support ligand-induced alterations in cellular adhesion. We established stable transfectants of mouse L1-2 pre-B cells with cDNA for human FPR (L1-2 FPR cells). The transfectants bind N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein with 1.4 x 10(5) sites per cell and a dissociation constant of 3.3 nM. Stimulation with FMLP induces a transient Ca2+ flux. FMLP also triggers adhesion of L1-2 FPR cells to TNF-alpha- or LPS-activated bEnd3 cells (mouse brain-derived endothelial cells) and to purified mouse VCAM-1. Binding is inhibited by Abs to VCAM-1 and to the alpha-chain of its lymphocyte receptor (the alpha 4 beta 1 integrin, VLA-4). Stimulation with FMLP does not induce a change in cell surface expression of alpha 4. Induced adhesion to VCAM-1 is rapid, detectable at the earliest times measurable (30 to 60 s after FMLP addition), and is inhibited by pertussis toxin. We conclude that FPR can mediate integrin activation not only in neutrophils but also in lymphocytes, and can trigger rapid adhesion via lymphocyte alpha 4 beta 1. The adhesion of lymphocytes is critical to their migration and targeting; our results suggest the possibility of manipulating adhesive responses through expression of chemoattractant receptors in lymphoid cells engineered for cellular therapy, allowing targeted adhesion and potentially migration in response to locally administered ligands.

Animals↗
PubMed2025

Genome-wide CRISPR screens identify critical targets to enhance CAR-NK cell antitumor potency.

Adoptive cell therapy using engineered natural killer (NK) cells is a promising approach for cancer treatment, with targeted gene editing offering the potential to further enhance their therapeutic efficacy. However, the spectrum of actionable genetic targets to overcome tumor and microenvironment-mediated immunosuppression remains largely unexplored. We performed multiple genome-wide CRISPR screens in primary human NK cells and identified critical checkpoints regulating resistance to immunosuppressive pressures. Ablation of MED12, ARIH2, and CCNC significantly improved NK cell antitumor activity against multiple treatment-refractory human cancers in vitro and in vivo. CRISPR editing augmented both innate and CAR-mediated NK cell function, associated with enhanced metabolic fitness, increased secretion of proinflammatory cytokines, and expansion of cytotoxic NK cell subsets. Through high-content genome-wide CRISPR screening in NK cells, this study reveals critical regulators of NK cell function and provides a valuable resource for engineering next-generation NK cell therapies with improved efficacy against cancer.

Humans↗
PubMed2026

Engineering the Vero Cell Lineage: Toward a Programmable Vaccine Manufacturing Platform.

Vero cells remain an indispensable continuous substrate for human viral vaccine manufacturing. Despite decades of empirical process optimization, intrinsic genomic instability, including segmental aneuploidy and dynamic chromatin rearrangements, continues to limit the durability of engineered phenotypes under sustained viral burden and bioreactor stress. Here, we review the expanding engineering toolkit for the Vero lineage across a three-layered functional framework: the membrane interface, cytoplasmic foundry, and nuclear blueprint, evaluating translational prospects at each level. Receptor transplantation and morphological reprogramming have broadened viral entry range and enabled suspension-adapted culture formats, while metabolic flux management and temporally controlled apoptosis modulation have addressed intracellular production bottlenecks, albeit often with trade-offs between productivity, biosafety, and long-term population stability. At the genomic level, targeted perturbations of transcriptional regulators and emerging epigenetic interventions offer more durable gains, yet expression drift, clonal heterogeneity, and karyotypic instability during extended passaging highlight the need for locus-level precision rather than constitutive trait installation. Looking forward, infection-responsive dynamic logic circuits and the systematic identification of Vero-specific genomic safe harbors could shift the paradigm toward a conditionally responsive manufacturing architecture. Collectively, these advances suggest a pathway for transitioning the Vero lineage from a passive, empirically optimized biological substrate into a conditionally responsive, genomically stable, and programmable platform for modern vaccine preparedness.

Vero cells↗
PubMed2001

Stem cell bioengineering.

Tissue engineering and cellular therapies, either on their own or in combination with therapeutic gene delivery, have the potential to significantly impact medicine. Implementation of technologies based on these approaches requires a readily available source of cells for the generation of cells and tissues outside a living body. Because of their unique capacity to regenerate functional tissue for the lifetime of an organism, stem cells are an attractive "raw material" for multiple biotechnological applications. By definition they are self-renewing because on cell division they can generate daughter stem cells. They are also multipotent because they can differentiate into numerous specialized, functional cells. Recent findings have shown that stem cells exist in most, if not all, tissues, and that stem cell tissue specificity may be more flexible than originally thought. Although the potential for producing novel cell-based products from stem cells is large, currently there are no effective technologically relevant methodologies for culturing stem cells outside the body, or for reproducibly stimulating them to differentiate into functional cells. A mechanistic understanding of the parameters important in the control of stem cell self-renewal and lineage commitment is thus necessary to guide the development of bioprocesses for the ex vivo culture of stem cells and their derivates.

Adult↗
PubMed2005

Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collagen-induced arthritis.

OBJECTIVE: Adult mesenchymal stem cells (MSCs) represent promising tools for therapeutic applications such as tissue engineering and cellular therapy. Recent data suggest that, due to their immunosuppressive nature, MSCs may be of interest to enhance allogeneic hematopoietic engraftment and prevent graft-versus-host disease. Using a murine model of rheumatoid arthritis (RA), this study investigated whether the immunosuppressive properties of MSCs could be of therapeutic value to inhibit reactive T cells in autoimmune diseases such as RA. METHODS: In mice with collagen-induced arthritis (CIA), we injected various doses of C3 MSCs at the time of immunization or booster injection, and subsequently evaluated the clinical and immunologic parameters. The immunosuppressive properties of MSCs were determined in vitro in mixed lymphocyte reactions with or without the addition of tumor necrosis factor alpha (TNFalpha). RESULTS: In the CIA model of arthritis, MSCs did not confer any benefit. Both the clinical and the immunologic findings suggested that MSCs were associated with accentuation of the Th1 response. Using luciferase-expressing MSCs, we were unable to detect labeled cells in the articular environment of the knee, suggesting that worsening of the symptoms was unlikely due to the homing of MSCs in the joints. Experiments in vitro showed that the addition of TNFalpha was sufficient to reverse the immunosuppressive effect of MSCs on T cell proliferation, and this observation was associated with an increase in interleukin-6 secretion. CONCLUSION: Our data suggest that environmental parameters, in particular those related to inflammation, may influence the immunosuppressive properties of MSCs.

Animals↗
PubMed2002

Stem cell engineering: the new generation of cellular therapeutics.

Hematopoietic stem cells (HSCs) supply all blood cells throughout life by making use of their self-renewal and multilineage differentiation capabilities. Over the last few years, transplantation of hematopoietic stem and progenitor cells from mobilized blood stem cells, umbilical cord blood and selected CD34+ cells has been used for treatment of patients with hematologic and non-hematologic malignances. The techniques have become available that allow the extensive proliferation, orderly differentiation, functional activation and gene transfer of hematopoietic stem/progenitor cells in ex vivo culture systems. These techniques have now developed to the point at which clinical trials are now underway in a variety of settings for the applications of hematopoietic stem cell transplantation, hematopoietic support after high-dose chemotherapy, immunotherapy of cancers, and gene therapy. The article will discuss the characteristics, detecting assays, surface markers, expansion, orderly differentiation, cell therapy and gene therapy of hematopoietic stem/progenitor cells. Except that, it will also discuss some advanced achievements of stem cell research, such as the multilineage differentiation of marrow-derived mesenchymal stem cells. Some results of different gene expression between stem cells and induced cells by gene chip analysis will be reported.

Animals↗