Download Development from Lateral Plate Mesoderm

Development from Lateral Plate Mesoderm
Lateral Plate Mesoderm
Somatopleure
Ectoderm
Dorsal Layer
Somatic (Parietal) Mesoderm
Somite
Intermediate
Mesoderm
Lateral Plate
Mesoderm
Coelom
Ventral Layer
Splanchnic (Visceral) Mesoderm
Endoderm
Splanchnopleure
• Coelom stretches from the neck region to the posterior of the body.
• Later it is subdivided into three separate cavities to envelop the thorax (pleural cavity),
heart (pericardial cavity) and abdomen (peritoneal cavity).
Mesodermal Development in Frog and Chick Embryos
Specification of the Cardiac Precursor Cells Requires BMP and Anti-Wnt
antiWnt
endocardium
epicardium
(homogenous) (heterogeneous)
signals
from
endoderm
atrium
ventricle
Wnt
BMP
BMP
antiBMP
Anti-Wnt + BMP + Fgf8
• atrial & ventricular myocytes
• endothelial lining
• cushion cells & valves
• Purkinje fibers (neuronal stimulation)
Wnt + BMP
blood & blood vessel
Migration and Differentiation of the Cardiac Precursor Cells
NCC
25 hrs
26 hrs
splanchnic LPM
(proliferation & migration)
(two independent differentiation)
• Cardiogenic mesoderm proliferates and migrates in close contact with the endodermal surface.
• Then, these migrating cardiogenic mesodermal cells form two separate endocardial primordia,
which will undergo independent differentiation.
Heart Tube Formation
28 hrs
29 hrs
(endocardial
tube
fusion)
beating
heart tube
by 33h
• Inward folding of the splanchnic mesoderm forms the foregut and renders two heart tubes to fuse
to generate the myocardium and the endocardium.
• The myocardium form the heart muscles.
• The endocardial cells produce many of the heart valves, and also regulate myocardial cell growth
and the nervous tissue placement.
Inhibition of Splanchnic Mesoderm Migration Causes
Two Separate Heart Tube Formation (Cardia Bifida)
Surgical Cutting
Ventral Midline
wild type zebra fish
wild type mouse
Foxp4 K.O.
miles apart mutant
Chick Cardia Bifida
Cardiac Myosin Light Chain Staining
Ventricular Myosin Staining
Expression of Tbx5 and RADH2 in Pre-Cardiac Mesoderm
Tbx5
RADH2
• Tbx5 (Anterior Border of Heart Field; Purple Staining)
• RADH2 (Retinaldehyde Dehydrogenase-2; Posterior Region of Heart Field; Orange Staining)
Cascade of Heart Development (1)
heart
valves
R
antiWnt
L
L
initial
contraction
umbilical veins
•
•
•
•
Flectin
L
ventricles  atriums
BMPs, Fgf8, and anti-Wnts coordinate initial induction of pro-cardiogenic factors.
Nkx2.5 and GATA4 induce each other to initiate cardiogenesis, and induces ANF.
GATA4 and MEF2C induce cardiac muscle specific proteins (e.g. cardiac actin, α-myosin HC, etc.).
Xin induction by Nkx2.5 and MEF2C mediates the cytoskeletal changes essential for heart looping.
Cascade of Heart Development (2)
heart
valves
R
antiWnt
L
L
initial
contraction
umbilical veins
•
•
•
•
Flectin
L
ventricles  atriums
The initial expression of Hand1, 2 is homogeneous in hear tube, but is, later, restricted.
Pitx2, specifically induced in the left-side by nodal, regulates the temporal expression of Flectin (ECM).
Truncus arteriosus initiates the contraction (pulsation) by 33 hrs. (cf. Na+-Ca2+ exchange pumps)
The ventricles are developed first, and then the atriums are formed.
Formation of Blood Cells and Blood Vessels from Blood Island
inner cells in blood island
I
II
II
Wnt
III
outer cells in blood island
Condensed aggregates of the hemangioblasts (extraembryonic mesodermal cells)
are called “blood islands” and they further differentiate to give rise to all the
precursor cells required for the hematopoiesis and the blood vessel formation.
Differentiation of Blood Island
Vasculogenesis : Initial Formation of Blood Vessel
• FGF accelerates proliferation
of endothelial precursor cells.
• VEGF induces differentiation of
endothelial precursor cells.
• Pericytes (periendothelial cells;
smooth muscle cell like) are
recruited by the signals from
angiopoietin and PDGF.
• Blood vessel integrity and cell
cycle quiescence of endothelial
cells are critically maintained
by the attachment of pericyte
cell layer.
Angiogenesis :
Blood Vessel Sprouting & Remodeling of Vascular Structures
• Locally formed blood vessels are later
linked via remodeling (angiogenesis).
• VEGF1 stimulates small blood vessels
sprouting from the arteries and veins.
• TGF-β establishes: ECM enrichment and
stabilization around the blood vessels.
• COL XVIII(18) is a critical MMP inhibitor to
stabilize the capillary structures.
• Endostatin is a C-term (182 aa) fragment
of COL18 and inhibits angiogenesis (antimetastatic effect).
Angiogenesis in Cancer Treatment
Benign Primary
Cell Death
Loss of
Growth Control
Hyperplasia
(Benign)
Hypoxia
Malignant
Primary
Angiogenesis
Malignant Secondary
Metastasized Tumor
(Secondary)
Metastasis
Survival
Blood
Circulation
Invasion & Escape
Vascularized Tumor
(Malignant)
Arterial and Venous Differentiation (1)
• Posterior blood vessels are separately formed from anterior blood vessels (linked to cardiogenesis).
• VEGF initiates angioblast differentiation for both peripheral arteries and veins.
• High doses of notch  Gridlock (+)  ephrin-B2  aorta forming cells
• Low doses of notch  Gridlock (-)  EphB4  cardinal vein forming cells
• Arteries and veins are formed separately and joined by capillary blood vessel fusions.
• During embryonic vascular development, anterior blood vessels derived from cardiac development
join peripheral blood vessels in the posterior regions by fusion.
Arterial and Venous Differentiation (2)
• Fusion of blood vessels is only permitted between ephrin-B2 positive arteries and EphB4 positive veins.
• Expansion of capillary structures increases the total area of blood vessels.
• Smaller diameters of the capillary blood vessels in the periphery decreases blood flow rate.
• Reduced blood flow increase the efficiency of capillary exchanges for nutrients, oxygen, and wastes.
Model for Collateral Blood Vessel Formation
Arteries
Nerves
Arteries + Nerves
Veins + Nerves
• In response to VEGF, endothelial cells are induced and become arteries first.
• These arteries then induce veins to form adjacent to them.
• New arterial vessels sprout from the arteries, and then induce venous vessels adjacent to them.
• Collateral migration and extension of arterial and venous vessel formation
• Artery and nerve developments are almost superimposable.
Evolutionary Conservation in Embryonic Circulation System
• Bulk of blood vessel formation in the extraembryonic regions during early embryogenesis
• Nutrient supply from the yolk (chick)
• Maternal nutrient supply in the imaginary yolk sac space (mammals)
Blood Cell Formation
Stem Cells ??
• Self-Renewing & Proliferation
• Pluripotent Differentiation
• Cell types with high turnover
- blood cells
- intestinal epithelium
- skin epidermis
- spermatocyte
Embryonic (Primitive) Hematopoiesis
• Initial blood cells are derived from the blood islands in the ventral & extraembryonic mesoderm.
• BMPs have been shown to be critical to induce the embryonic hematopoietic stem cells (HSCs).
• Production of these blood forming stem cells are transitory.
Definitive (Adult) Hematopoiesis
• In chick, the life-time lasting HSCs are originated from the mesodermal
Aorta Section
area surrounding aorta called aorta-gonad-mesonephros (AGM) region.
• In mammals, HSCs may originate from yolk sac and placenta.
• These stem cells later colonize the fetal liver, and by the time of birth, most
HSCs populate in the bone marrow (major adult blood formation site).
AGM
• Hoxb-4 is a critical adult HSC marker. (cf. Forced expression of Hoxb-4 in
embryonic HSC can populate primitive HSCs in the adult bone marrows.)
• Wnt, Notch, and Tie2 signaling maintains HSCs in bone marrow.
Traveling of HSC during Development
HSC Maintenance by BM Osteoblasts
Current Model for Hematopoiesis
• 1 in 10,000 blood cells is a HSC.
• A transcription factor, SCL specifies and
maintains HSCs.
• HSCs give rise to lineage specific stem
cells producing either CMPs (blood cells)
or CLPs (immune system).
• The immediate progenies of CMPs
including MEP and GMP, or CLPs
including pro-NK, pro-T, and pro-B cells
are destined to differentiate into more
restricted cell types.
• The paracrine factors involved in blood
cell and lymphocyte formation are called
cytokines.
•
•
•
•
•
CMP : Common Myeloid Precursor
CLP : Common Lymphoid Precursor
MEP : Megakaryocyte/Erythroid Precursor
GMP : Granulocyte/Monocyte Precursor
BFU-E : Erythroid Progenitor Cell
The Paracrine Factors
(i.e. Cytokines)
Involved in
Blood Cell and Lymphocyte
Differentiation
• IL : interleukin
• SDF-1 : stromal-derived factor-1
• SCF : stem cell factor
• G-CSF : granulocyte colony stimulating factor
• M-CSF : macrophage colony stimulating factor
• GM-CSF : granulocyte-macrophage CSF
• TGF-β : transforming growth factor-beta
• MHC : major histocompatibility complex
• EPO : erythropoietin
• Tpo : thrombopoetin