Cell-cell communication

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Cell-cell communication in development Review of cell signaling, paracrine and endocrine factors, cell death pathways, juxtacrine signaling, differentiated state, the extracellular matrix, integrins, epithelial-mesenchymal transition:

Cell-cell communication in development Review of cell signaling, paracrine and endocrine factors, cell death pathways, juxtacrine signaling, differentiated state, the extracellular matrix, integrins , epithelial- mesenchymal transition Mitesh Shrestha Central Department of Biotechnology Tribhuvan University

Review of cell signaling:

Review of cell signaling Part of a complex system of communication that governs basic activities of cells and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue homeostasis. Errors in cellular information processing are responsible for diseases such as cancer, autoimmunity, and diabetes. By understanding cell signaling, diseases may be treated more effectively and, theoretically, artificial tissues may be created.


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Paracrine factors:

P aracrine factors Form of cell-cell communication in which a cell produces a signal to induce changes in nearby cells, altering the behavior or differentiation of those cells . Signaling molecules known as paracrine factors diffuse over a relatively short distance (local action ). Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome .

Endocrine factors:

Endocrine factors When cells need to transmit signals over long distances, they often use the circulatory system as a distribution network for the messages they send. In long-distance  endocrine signaling , signals are produced by specialized cells and released into the bloodstream, which carries them to target cells in distant parts of the body. Signals that are produced in one part of the body and travel through the circulation to reach far-away targets are known as hormones . In humans, endocrine glands that release hormones include the thyroid, the hypothalamus, and the pituitary, as well as the gonads (testes and ovaries) and the pancreas. Each endocrine gland releases one or more types of hormones, many of which are master regulators of development and physiology. For example, the pituitary releases  growth hormone  ( GH ), which promotes growth, particularly of the skeleton and cartilage. Like most hormones, GH affects many different types of cells throughout the body. However, cartilage cells provide one example of how GH functions: it binds to receptors on the surface of these cells and encourages them to divide.

Endocrine factors:

Endocrine factors

Cell Death Pathways:

C ell D eath P athways Cell death is a crucial process during development, homeostasis and immune regulation of multicellular organisms, and its dysregulation is associated with numerous pathologies. Cell death is often induced upon pathogen infection as part of the defense mechanism, and pathogens have evolved strategies to modulate host cell death. Four major types of programmed cell death, namely apoptosis, necrosis, autophagic cell death and pyroptosis.

Apoptosis: Pathways:

Apoptosis: Pathways Death Ligands Effector Caspase 3 Death Receptors Initiator Caspase 8 PCD DNA damage & p53 Mitochondria/Cytochrome C Initiator Caspase 9 “Extrinsic Pathway” “Intrinsic Pathway”


STAGES OF APOPTOSIS Sherman et al., 1997 Induction of apoptosis related genes, signal transduction


membrane blebbing & changes mitochondrial leakage organelle reduction cell shrinkage nuclear fragmentation chromatin condensation APOPTOSIS: Morphology Hacker., 2000


p53 Apoptosis events Initiator caspases 6, 8 , 9,12 Activators of initiator enzymes Apoptotic signals Execution caspases 2, 3, 7 APOPTOSIS: Signaling & Control pathways I Externally driven Internally driven Cytochrome C Externally driven Activation mitochondrion


p53 External Internal Apoptosis events Initiator caspases 6, 8 , 9,12 Activators of initiator enzymes Apoptotic signals Execution caspases 2, 3, 7 Inhibitors of apoptosis APOPTOSIS: Signaling & Control pathways II Inhibitors Externally driven Internally driven Cytochrome C Externally driven Survival factors Bcl2 Inhibition


H 2 O 2 Growth factor receptors casp9 Bcl2 PI3K Akt BAD Apaf1 Cyt.C ATP The mitochondrial pathway casp3 casp3 IAPs Smac/ DIABLO AIF Bax Bax p53 Fas Casp8 Bid Bid Bid DNA damage Pollack etal ., 2001

Juxtacrine signaling:

J uxtacrine signaling Juxtacrine signaling (or contact-dependent signaling) is a type of cell / cell or cell / extracellular matrix signaling in multicellular organisms that requires close contact.

Cell Differentiation:

Cell Differentiation Normal process by which a cell becomes increasingly specialized in form and function. P rocess by which cells develop special structures or lose certain structures to enable them to carry out specific functions. The classic example is the process by which a zygote develops from a single cell into a multicellular embryo that further develops into a more complex fetus.

Cell Differentiation:

Cell Differentiation The process of cellular differentiation is regulated by transcription factors and growth factors , and results in expression or inhibition of various genes between the cell types, thereby resulting in varying proteomes between cell types. Cellular differentiation is regulated by many processes and substances including cell size, shape, polarity, density, metabolism, and extracellular matrix composition . Under the influence of these external factors, each cell is programmed to differentiate and eventually mature into its specialized cell such as heart, muscle, skin, and brain cells . Hence, cells become differentiated to form specialized cells. The structure of each cell is adapted to perform the specific functions of the cell.

Regulation By Cell Shape:

Regulation By Cell Shape hMSCs allowed to adhere, flatten, and spread underwent osteogenesis , while unspread , round cells became adipocytes. Cell shape regulated the switch in lineage commitment by modulating endogenous RhoA activity. Expressing dominant-negative RhoA committed hMSCs to become adipocytes, while constitutively active RhoA caused osteogenesis . However , the RhoA -mediated adipogenesis or osteogenesis was conditional on a round or spread shape, respectively, while constitutive activation of the RhoA effector, ROCK, induced osteogenesis independent of cell shape.

Cell Differentiation:

Cell Differentiation

Cell Differentiation:

Cell Differentiation To develop a multicellular organisms, cells must differentiate to specialize for different functions. Three basic categories of cells make up the mammalian body: Germ cells, Somatic cells, and Stem cells.

Cell Differentiation:

Cell Differentiation The determination of different cell types (cell fates) involves progressive restrictions in their developmental potentials. When a cell “chooses” a particular fate, it is said to be determined, although it still "looks" just like its undetermined neighbors. Determination implies a stable change - the fate of determined cells does not change. Differentiation follows determination, as the cell elaborates a cell-specific developmental program. Differentiation results in the presence of cell types that have clear-cut identities, such as muscle cells, nerve cells, and skin cells.

Differential gene expression is not a result of differential loss of the genetic material, DNA, except in the case of the immune system. That is, genetic information is not lost as cells become determined and begin to differentiate.:

Differential gene expression is not a result of differential loss of the genetic material, DNA, except in the case of the immune system. That is, genetic information is not lost as cells become determined and begin to differentiate.

Mechanisms of cellular determination:

Mechanisms of cellular determination How do cells become different from their parent cells? How do two identical daughter cells become different from one another? How might one daughter cell become a neuron, while the other daughter cell becomes a skin cell? In some cases, determination results from the asymmetric segregation of cellular determinants . However, in most cases, determination is the result of inductive signaling between cells.

Mechanisms of cellular determination:

Mechanisms of cellular determination Asymmetric segregation of cellular determinants P-granule segregation during the early embryonic divisions of the nematode Caenorhabditis elegans

Mechanisms of cellular determination:

Mechanisms of cellular determination Inductive signal One group of cells influences the development of another group of cells.

Pattern formation:

Pattern formation How do organs develop in their proper positions? How do cells "know" where they are within a developing organism? Pattern formation concerns the processes by which cells acquire positional information . There are two general models for how patterns form: use of a morphogen gradient , and sequential induction.

Morphogen gradient:

Morphogen gradient The morphogen gradientmodel involves the production and release of a diffusible chemical signal called a morphogen . Morphogen release creates a concentration gradient, with high concentrations of morphogen close to the source, and low concentrations farther away from the source. Exposure to different threshold levels of morphogen leads to different cell fates.

Sequential induction:

Sequential induction The sequential inductionmodel involves the production and release of a series of chemical signals. Signal 1 leads to the blue fate and production of signal 2. Signal 2 is received by neighbor cells, and leads to the red fate and production of signal 3. Signal 3 is then received by neighbor cells, and leads to the purple fate. In contrast to the morphogen gradient model, multiple chemical signals are required to create the pattern.

Extracellular Matrix:

E xtracellular Matrix Extracellular matrix (ECM) is a non-ce llular three-dimensional macromolecular network composed of collagens, proteoglycans/ glycosaminoglycans , elastin, fibronectin , laminins , and several other glycoproteins. Matrix components bind each other as well as cell adhesion receptors forming a complex network into which cells reside in all tissues and organs. Cell surface receptors transduce signals into cells from ECM, which regulate diverse cellular functions, such as survival, growth, migration, and differentiation, and are vital for maintaining normal homeostasis. ECM is a highly dynamic structural network that continuously undergoes remodeling mediated by several matrix-degrading enzymes during normal and pathological conditions. Deregulation of ECM composition and structure is associated with the development and progression of several pathologic conditions.

Extracellular matrix (ECM):

Extracellular matrix (ECM) Network of macromolecules (proteins, glycoproteins, proteoglycans and polysaccharides) Provides mechanical support for cells Influences the behavior and differentiation of cells which are in contact with it The main receptors of cells, mediating the interaction of cells with ECM, are known as integrins


Integrin T ransmembrane protein which extracellular part is receptor for adhesion molecules of extracellular matrix Heterodimeric molecules in which the  and  subunits are noncovalently bonded  subunit has four Ca2+ -binding domain on its extracellular part of polypeptide chain  subunit bears a number of cysteine-rich domains on its extracellular part of polypeptide chain


Integrin Necessary component of all Metazoans (from sponges to humans) Any member of the large family of transmembrane proteins that act s as receptor for adhesion molecules of extracellular matrix It plays a role in the attachment of the cell to the ECM and to other cells, and in signal transduction between ECM and the cell. This transduction is signaling from ECM to the cell (outside-in signaling) as well as signaling from the cell to extracellular space (inside-out signaling)

Stages of integrin receptor :

Stages of integrin receptor Low affinity receptor (cells are not activated) High affinity receptor (activated cells) High affinity receptor and clustering of integrin (high avidity activation)

Integrin activation in hematopoietic cells:

Integrin activation in hematopoietic cells Typical example is activation of platelets Platelet integrin is maintained in the inactive state with low affinity for its extracellular ligand – fibrinogen After platelet stimulation integrin is rapidly activated to high affinity leading to fibrinogen binding

Epithelial – Mesenchymal Transition:

Epithelial – Mesenchymal Transition An epithelial- mesenchymal transition (EMT) is a biologic process that allows a polarized epithelial cell , which normally interacts with basement membrane via its basal surface, to undergo multiple biochemical changes that enable it to assume a mesenchymal cell phenotype , which includes enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, and greatly increased production of ECM components. The completion of an EMT is signaled by the degradation of underlying basement membrane and the formation of a mesenchymal cell that can migrate away from the epithelial layer in which it originated.

EMT Markers:

EMT Markers Proteins that increase in abundance N-cadherin Vimentin Fibronectin Snail1 (Snail) Snail2(Slug) Twist Goosecoid FOXC2 Sox10 MMP-2 MMP-3 MMP9 Integrin vß6 Proteins that decrease in abundance E-cadheren Desmoplakin Cytokeratin Occludin Proteins whose activity increases ILK GSK-3ß Rho Proteins that accumulate in the nucleus ß-catenin Smad-2/3 NF- ß Snail1 (Snail) Snail2 (Slug) Twist



Three classes of EMTs:

Three classes of EMTs Type 1 EMT: EMT during implantation, embryogenesis , and organ development Type 2 EMT: EMT associated with tissue regeneration and organ fibrosis Type 3 EMT: EMT associated with cancer progression and metastasis

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