Cellular heterochrony and neoplasia

Neoplastic change in a cell represents a cellular ‘macroevolutionary’ event. Through variation or rearrangement of regulatory genes, neoplastic cells reiterate the expression of normally quiescent ancestral, juvenile, or embryonic traits and behaviour at an inappropriate stage in their ontogeny. The author has coined the term ‘cellular heterochrony’ to illustrate analogic similarities in the molecular modes of evolutionary change of both anaplastic cancer cells and the heterochronic, paedomorphic evolution of organisms.In these pages, anaplasia is considered to be part of a larger biological phenomenon. A theory regarding the role of prolactin and thyroxine in tumourigenesis is presented to explain the atavistic or heterochronic development and possible metamorphosis of retrodifferentiated malignant cells.     

Cellular senescence and atherosclerosis

Most recent texts on atherosclerosis do not consider cellular senescence. Texts that do take this up often emphasize smooth muscle cells. This paper presents some evidence for the role of cellular senescence in atherogenesis, and points out that the cells of the intimal endothelium may be equally important in this respect.     

Molecular and Cellular Immuno-Engineering

Genetically-encoded biosensors based on fluorescence proteins(FPs)and fluorescence resonance energy transfer(FRET)have enabled the specific targeting and visualization of signaling events in live cells with high spatiotemporal resolutions.Single-molecule FRET biosensors have been successfully developed to monitor the activity of a variety of signaling molecules,including tyrosine/serine/threonine kinases.We have a developed a general high-throughput screening(HTS)method based on directed evolution to develop sensitive and specific FRET biosensors.We have first applied a yeast library and screened for a mutated binding domain for phosphorylated peptide sequence.When this mutated binding domain and the peptide sequence are connected by a linker and then concatenated in between a pair of FRET FPs,a drastic increase in sensitivity can be achieved.It has also been increasingly clear that controlling protein functions using lights and chemical compounds to trigger allosteric conformational changes can be applied to manipulate protein functions and control cellular behaviors.In this work,we first engineered a novel class of machinery molecules which can provide a surveillance of the intracellular space,visualizing the spatiotemporal patterns of molecular events and automatically triggering corresponding molecular actions to guide cellular functions.We have adopted a modular assembly approach to develop these machinery molecules.We engineered such a molecule for the sensing of intracellular tyrosine phosphorylation based on fluorescence resonance energy transfer(FRET)and the consequent activation of a tyrosine phosphatase(PTP)Shp2,which plays a critical and positive role in various pathophysiological processes~([1-3]).We have further integrated this machinery molecule to the"don't eat me"CD47 receptor SIRPa on macrophages such that the engagement of SIRPa and its activation of naturally negative signals will be rewired to turn on the positive Shp2 action to facilitate phagocytosis of red blood cells and target tumor cells,initiated by the specific antigen-targeting antibodies and their interaction with Fcg receptors.Because of the modular design of our engineered molecule,our approach can be extended to perform a broad range of cell-based imaging and immunotherapies,and hence highlight the translational power in bridging the fundamental molecular engineering to clinical medicine.We have also integrated with lights and ultrasound to manipulate the molecular activation of genes and enzymes,which allowed us to control the cellular functions of immunocells with high precision in space and time.     

Cellular and Matrix Contributions to Tissue Construct Stiffness Increase with Cellular Concentration

The mechanics of bio-artificial tissue constructs result from active and passive contributions of cells and extracellular matrix (ECM). We delineated these for a fibroblast-populated matrix (FPM) consisting of chick embryo fibroblast cells in a type I collagen ECM through mechanical testing, mechanical modeling, and selective biochemical elimination of tissue components. From a series of relaxation tests, we found that contributions to overall tissue mechanics from both cells and ECM increase exponentially with the cell concentration. The force responses in these relaxation tests exhibited a logarithmic decay over the 3600 second test duration. The amplitudes of these responses were nearly linear with the amplitude of the applied stretch. The active component of cellular forces rose dramatically for FPMs containing higher cell concentrations.An erratum to this article can be found at     

Cellular haemangioma

Summary Light and electron microscopic studies were conducted on the immature vascular tumors of two infants, containing various stages of differentiation of the blood vessels and both benign haemangioendotheliomas and haemangiopericytomas. We were able to confirm the existance of two kinds of hyperplastic, immature cells i.e. endothelial cells and pericytes in the same tumor. Presence of crystalloid inclusions in the endothelial cells and absence of the Weibel-Palade bodies, as well as a deficiency in factor VIII-related antigen and no tissue fibrinolytic activity, suggested that the endothelial cells in these lesions were immature. Electron microscopic studies appear more decisive in the diagnosis of heterogenous cellular vascular tumors than light microscopy and if available should be used to aid in the final diagnosis. The authors propose that the term cellular haemangioma would be more appropriate in describing this vascular entity.Part of this work was presented at the University of Michigan Plastic Surgery Seminar, Ann Arbor, May 1981, and Second International Symposium on Biology of the Vascular Endothelial Cell, Cambridge, GB, September 1981These studies were supported by the Louise Lambertson Vaughn Bequest for Haemangioma Research     

Cellular engineering

Cellular engineering applies the principles and methods of engineering to the problems of cell and molecular biology of both a basic and applied nature. As biomedical engineering has shifted from the organ and tissue level to the cellular and sub-cellular level, cellular engineering has emerged as a new area. A cornerstone of much of this activity is cell culture technology, i.e., the ability to grow living cells in the artificial environment of a laboratory. Cellular engineering includes the role of engineering in both basic cell biology research and in the making of products which use living cells, e.g., tissue engineering and bioprocess engineering. The former involves the use of living cells in the development of biological substitutes for the restoration or replacement of function, and the latter the use of living cells to manufacture a biochemical product, e.g., throught the use of recombinant DNA technology. In fact, as biomedical engineering has expanded to include the cellular level, and bioprocess engineering has shifted in interest from microbial organisms to include mammalian cells, there are intellectual issues in which an interest is shared by these two formerly separate areas of engineering activity. Cellular engineering thus transcends the field of biomedical engineering. The lecture was delivered on April 22, 1991 by R.M. Nerem, Parker H. Petit Professor for Engineering in Medicine, School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332-0405.     

Cellular carboxypeptidases

Summary: This article focuses on four human carboxypeptidases (CPs): two metallo-CPs and two serine CPs. The metallo-CPs are members of the so-called B-type regulatory CP family, as they cleave only the C-terminal basic amino acids Arg or Lys. The plasma membrane-bound CPM and the mainly, but not exclusively, intracellular CPD are surveyed from this group of enzymes. These enzymes can regulate pep tide hormone activity at the cell surface and possibly intracellularly after receptor-mediated endocytosis and may also participate in peptide hormone processing. The serine CPs, as their name indicates, contain a serine residue in the active center essential for catalytic activity that reacts with organophosphorus inhibitors, Prolylcarboxypeptidase (PRCP) (angiotensinase C) and deamidase (cathepsin A, lysosomal protective protein) are discussed here. These two enzymes are highly concentrated in lysosomes: however, they may also be active extracellularly after their release from lysosomes in soluble form or in a plasma membrane-bound complex. Whereas deamidase cleaves a variety of peptides with C-terminal or penultimate hydrophobic residues (e.g. substance P, angiotensin I, bradykinin, endothelin, fMet-Leu-Phe), PRCP cleaves only peptides with a penultimate Pro residue (e.g. des-Arg°-bradykinin, angiotensin II). These enzymes may also be involved in terminating signal transduction by inactivating peptide ligands after receptor endocytosis.