1. Tissue dynamic and Morphogenesis Dept. Physiology Chang Gung University J. K. Chen, Professor

2. Morphogenesis Morphogenesis refers to the structural changes and its underlying mechanisms Morphogenic processes are important in tissue dynamics, and in practical aspects of tissue reconstruction, repair and engineering

3. Dynamic state of tissues Tissue homeostasis: the normal steady-state function of tissue. Tissue repair: the integration procedure following grafting of tissue is expected to display components of tissue repair processes. Tissue formation: the way tissues form is of key concern to cellular therapies. The younger the cell source, the more organogenic potential it possesses.

4. Processes that lead to the evolution of a functional tissue Induction : many tissues will not begin to develop until cells of different types come into physical contact with one another. Once they are in contact, at least one of the layers of the two tissue types undergoes reorganization. The presence of one cell type is needed to induce a change in the other.

7. Transdifferentiation Adult cell can transdifferentiate from one cell type to another. In particular, mesenchyme and epithelial can transform due to expression of a variety of genes. These transdifferentiation pathways are of importance to tissue engineering.

9. Cellular processes involved in morphogenesis Cell migration Tissue sorting Tissue patterning by cell death

10. Cell migration Bone marrow stem cells can be induced to migrate out of the marrow into blood circulation by infusing chemotactic growth factors into the patient. Changes in cell-cell adhesion may initiate the migration of a cell population.

11. Mobilization and homing J Clin Invest., 115, 572, 2005

12. Biochemical process of cell migration Step 1 : protrusion of membrane lamellopodia, local actin polymerization plays an important role. Step 2 : adhesion to the matrix occurs via integrins, providing a link to the actin cytoskeleton. Step 3 :contraction of the cytoplasm by myosin based-motor. Step 4 : rear release and cell displacement Step 5 : the remaining integrins are recycled by endocytosis and intracellular diffusion of the integrin vesicles to the leading edge.

14. Cellular processes involved in morphogenesis

15. Initiation of morphogenesis To initiate the morphogenic process, the present state (the initial cellular arrangement) must be destabilized. Some of the initial molecular processes during morphogenesis are those involved in the expression of surface protein and alteration in the extracellular matrix.

18. Cell death Programmed cell death : cells have to die if they don’t pass certain check point in the cell cycle. For instance, cells need to die in a controlled fashion to produce the finger pattern during development. Biochemically, there are 2 major events involved : a cascade of caspase activation. a cascade of caspase activation. a loss of mitochondrial membrane function. a loss of mitochondrial membrane function. a large opening in the mitochondrial a large opening in the mitochondrial membrane marks the point of no return in membrane marks the point of no return in this process. this process.

20. Unerlying biochemical process Three different mode of apoptosis induction : 1. an external murder signal 2. removal of an extracellular 2. removal of an extracellular survival signal survival signal 3. a “suicide” program initiated 3. a “suicide” program initiated by an external stress by an external stress

22. Fas signaling and mechanism of blocking by DcR3 : malfuntion of cell signaling leads to breakdown of normal cell- coordination process