Cell and extracellular matrix during the morphogenesis of tissue and organs

Professor Ming Hao Zheng, PhD, DM, FRCPath

Minghao.zheng@uwa.edu.au

Objectives & Outcomes

• Describe the sequential events of tissue and organ development during embryogenesis;

• Describe the role of extracellular matrix and its dynamics in tissue regeneration;

• Enable to give examples on the role of growth factors and extracellular matrix molecules in organogenesis.

Morphogenesis of tissue and organ

• Beginning at the Formation of Primitive streak on the disc.

• Embryonic ectoderm : epidermis, nervous system, retina of the eye, etc.

• Embryonic endoderm : endothelial linings.

• Embryonic mesoderm : smooth muscular coats, connective tissues, vessels, cardiovascular system, blood, bone marrow, reproductive and excretory organs.

Organ-genetic period of embryonic development.

• 3rd Week : 5 weeks after the first day of last normal menstrual period.

• 4 phases : growth, morphogenesis, differentiation, maturation.

• Morphogenesis : complex interaction occurring in an order sequence, cell movement and cell transformation (EMT, MET) and program cell death.

Development of the skin

• Four to five weeks.

• Epidermis – derived from surface ectoderm.

• Dermis – derived for mesoderm.

• But …Melanocytes from neural crest.

Development of cartilage

• Five weeks

Paraxial mesoderm somites Condensation of mesenchymal cells

Chondrification centreschondroblasts

Hyaline Fibro Elastic

Development of bone

• Paraxial mesoderm to form somites.

• Intra-membranons ossification (Flat bones)

Membrane sheath

VascularizationOsteoid matrix deposition

Condensation of mesenchymal cells

Development of bone - continued

Intra-cartilagionous ossification (Endochondral ossification : long bones)

Condensation of mesenchymal cells

Cartilage tissue

Hyperthropic

Vasculization and osteoblast differentiation

Osteoblast, haversian system, osteocyte,osteoclast

Development of skeletal muscle

• Seven weeks

• Myotome regions of the somites (mesoderm)

• Mesenchymal cells

myoblastFusion

myotubes

Development of smooth muscle

• Somatic mesoderm – vessels smooth muscle

• Mesenchymal cells – myoepithelial cells in glands

• Splanchnic mesenchyme – Around endoderm – other smooth muscle

• Remain mononuclear

Development of Cardiac muscle

• Four weeks

• Lateral splanchnic mesoderm

• Cardiac muscle fibers arise form single cells.

Development of peripheral nervous system (PNS)• Neural crest cells

• Cranial, spinal visceral nerves and cranial, spinal and autonomicganglia

• Bipolar of sensory cells

• Satellite cells

• Schwann cells

• Connective tissue outside the capsule.

• Epithelial – mesenchymal transformation (EMT)

neural crest, cardiac cushion cells, midline cells of the palate, dermis of the skin, limb musculature, sclerofome.

- involved in the developmental and oncogenic pathways regulating in tumor growth, angiogenesis, metastasis, as well as the reprogrammation of specific gene repertoires ascribed to both epithelial and mesenchymal cells.

• Mesenchymal – Epithelial transformation (MET)

kidney tubules, nephrogenic blastema, endocardium, somities.

Cell and matrix molecule interactionMatrix proteins• Fibrous structural proteins: collagen, laminis, fibrinectin,

vitronectin and elastin.

• Specialized proteins: growth factors, small matricellular proteins, small integrin-binding glycoproteins (SIBLINGD).

• Proteoglycans;

• Matrixc degrading enzymes: MMP; serine protease; cysterine protease

Cells• Cell proliferation

• Survival

• Shape

• Migration

• Differentiation

Organogenesis & regeneration

ECM interaction in the stem cell niche

Stem-cell niche refers to a microenvironment, within the specific anatomic location where stem cells are found, which interacts with stem cells to regulate cell fate. The word 'niche' can be in reference to the in vivo or in vitro stem-cell microenvironment.

Cell and matrix molecule interaction

• Growth factors– BMP/TGFβ, Wnt Signaling

• Cell adhesion molecules

• Cell – ECM interactions: Integrin and receptors;

• Cell-Cell interactions: Eph/ephrin family;

• Matrix molecules and their ligands

Bone morphogenetic proteins(BMP)

Functions of BMPs

• Binds to heparitin sulfate, heparin, type IV Collagen;

• BMP regulates cell type specification, maturation, apoptosis, chemotaxis, mitosis, differentiation, extracellular matrix production;

• BMP-2 K/O – embryonic lethal. Heart

• BMP-4 K/O – no mesoderm induction

• BMP-7 K/O – kidney, eye development

• Numbers of clinical applications

Functions of Cadherin (N, E, C)

• Mediate homophilic interaction during EMT/MET

• N-Cadherin K/O : ill-formed somites, abnormal neural tubes, loosely organised myocardium. No EMT.

• E-Cadherin K/O : MET ,

trophectoderm fail to form, basolateral domain of epithelinum

• Cadherin’s partner : Catenins (αβ) via phosphorylation .

• Concomitant with integrin for cell adhesion.

Integrins as ECM receptors

• Heterodimeric trans membrane protein αβ subunits.

• 15 sub-types of α and 8 β.

• Arginin-glycine-aspartate (RGD) sequence and the neighbouring modulatory site

Integrin family of receptors and their extracellular ligands

Regenerative Medicine

Regenerative medicine replaces or regenerates human cells tissue or organs to establish normal function

Regenerative medicine refers a group of biomedial approaches to healing that involve stem cells.[1] One is the injection of stem cells

or progenitor cells ; another the induction of regeneration by introduced substances such as growth factors and sacffold ; and a

third is transplantion of in vitro grown organs and tissues.

Mason C, Regen Med, 2008

http://en.wikipedia.org/wiki/Stem_cellhttp://en.wikipedia.org/wiki/Organ_transplantation

Three key components for Regenerative medicine Genes control the program of cell differentiation and proliferation

Cells produce various matrix

Matrix served as scaffold for cell growth/differentiation

Matrix - Scaffolding

Cells - functions

Genes – growth factors/restoration

Tissue Organ

West Australian24th Jul 2013, Health, Page 1-3,

In the 16 Century…

Italian surgeon in Bologna Dr Gasparo Tagliacozzi used a flap of skin from the inner aspect of the upper arm to carve the shape of the patient’s nose. He then stitched it to the forehead and inner surface of the cheek, leaving a slender attachment to the arm to maintain blood supply until circulation was re-established from the face.

Scottish surgeon John Hunter (1728 –1793)Autograft of a cock’s claw to its comb

http://upload.wikimedia.org/wikipedia/en/8/86/John_Hunter_2206660627.jpghttp://upload.wikimedia.org/wikipedia/en/8/86/John_Hunter_2206660627.jpg

Last 200 year…

• First Nobel prize winner of Medicine in USA.

• Organs from a person killed accidentally would be suitable for “organ transplantation” (1907).

• “Tissues or cells could be obtained from patients and grown in vitro from transplantion”(1906).

• Ross Harrison proposed a term of independent cell growth later called “cell culture” (1908).

Alexis Carrel (1873-1944)

Biotherapeutics in the Twentieth Century

• Nobel prize winner of Medicine

“The efficacy of skin transplantation and established failure of a skin graft to ‘take’ was the result of immunological rejection” (1944).Sir Peter Medawar

(1915-1987)

• Morphogenesis of tissues and organs starts from cell and matrix molecule interactions.

• Morphogenesis is a sequential multi step cascade.

• Tissue morphogenesis is not only dependent of changes in either cell shape or oriented cell division but also relies exclusively on cells exchanging their neighbours.

• Regeneration recapitulates embryonic development.

Key messages

Cell and extracellular matrix during the morphogenesis of tissue and organsObjectives & OutcomesMorphogenesis of tissue and organOrgan-genetic period of embryonic development.Development of the skinDevelopment of cartilageDevelopment of boneDevelopment of bone - continuedDevelopment of skeletal muscleDevelopment of smooth muscleDevelopment of Cardiac muscleDevelopment of peripheral nervous system (PNS)Slide Number 13Cell and matrix molecule interactionSlide Number 15Cell and matrix molecule interactionBone morphogenetic proteins(BMP)Functions of BMPsFunctions of Cadherin (N, E, C)Integrins as ECM receptorsIntegrin family of receptors and their extracellular ligandsRegenerative MedicineSlide Number 23Slide Number 24In the 16 Century…Scottish surgeon John Hunter (1728 – 1793)��Autograft of a cock’s claw to its combLast 200 year…Biotherapeutics in the Twentieth CenturySlide Number 29Slide Number 30Slide Number 31Slide Number 32