Heart Dev 1 Flashcards
Morphogenesis
biological process that shapes organs and structures during development. It involves changes in cell shape, movement, and organization to form complex structures from simple ones.
🔹 Step 1: Cell Proliferation (Growth & Multiplication)
✔ Cells rapidly divide to create enough cells for organ formation. [Cells proliferate (multiply) in specific areas like the primitive streak]
✔ Controlled by growth factors like FGF (Fibroblast Growth Factor) & Wnt signaling.
🔹 Step 2: Differentiation (Becoming Specialized)
✔ Stem cells turn into specific cell types (e.g., heart cells, bone cells, neurons).
✔ This happens through the expression of specific genes.
🔹 Example: In heart development, some cells become cardiomyocytes (heart muscle cells) while others become endothelial cells (blood vessels).
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🔹 Step 3: Cell Migration (Moving to the Right Location)
✔ Cells move to their correct positions in the forming organ. [They migrate (move) to different locations to form specific structures, such as the cardiac crescent for the heart or the neural tube for the brain & spinal cord.]
✔ Guided by chemical signals (chemotaxis) & mechanical forces.
🔹 Example:
In heart development, cardiac progenitor cells migrate from the primitive streak to form the cardiac crescent.
Neural crest cells migrate to form parts of the heart valves and vessels.
🔹 Analogy: Imagine organizing different workers at the right spots before constructing a building.
🔹 Step 4: Extracellular Matrix (ECM) Deposition & Remodeling
✔ ECM = The “scaffolding” that supports cells.
✔ Made of proteins like collagen, fibronectin, and laminin.
✔ ECM helps cells attach, communicate, and move.
✔ Certain cells remodel ECM to shape tissues, e.g.:
Osteoblasts (build ECM in bones).
Osteoclasts (break down bone ECM).
Fibroblasts (produce ECM components like collagen in tissues).
🔹 Example:
In the developing heart, ECM proteins help guide cardiac cell migration and chamber formation.
If ECM isn’t properly remodeled, congenital heart defects can occur.
🔹 Analogy: ECM is like scaffolding for construction—it helps shape the structure, but some parts need to be removed or rearranged.
🔹 Step 5: Tissue Folding & Convergence
✔ Cells change shape & organize into 3D structures.
✔ Mechanical forces & cell adhesion proteins help tissues fold.
🔹 Example:
The heart starts as a simple tube, but folds into a loop (heart looping) to create chambers.
Neural tube closure in early brain and spinal cord development.
🔹 Analogy: Think of folding a flat piece of paper into a complex origami shape—cells do this to form organs!
🔹 Step 6: Apoptosis (Programmed Cell Death)
✔ Unneeded cells are removed to refine organ shape.
✔ Prevents extra tissue from forming in the wrong places.
✔ Controlled by genes like Bcl-2 and Caspases.
🔹 Example:
Fingers develop as a solid mass, but apoptosis removes webbing between them.
In the heart, apoptosis helps sculpt the heart chambers.
🔹 Analogy: Like erasing pencil lines after sketching a drawing to refine the final image.
🔹 Morphogenesis in Heart Development
In the image, the heart undergoes morphogenesis as it transforms from a simple structure into a fully developed organ:
1️⃣ Day 15 (Cardiac Crescent) → The heart starts as two regions of cells (cardiac progenitors).
2️⃣ Day 21 (Linear Heart Tube) → The cells merge into a tube-like structure, with different regions forming specific parts of the heart.
3️⃣ Day 28 (Heart Looping) → The tube bends and folds, creating the early chambers of the heart.
4️⃣ Day 50 (Mature Heart) → The heart develops separate chambers, valves, and blood vessels for proper circulation.
Primitive Streak
✔ What is it?
The primitive streak is the first visible structure that defines the body’s symmetry (left-right, head-tail) during early development.
It forms on the back of the embryo at around Day 15 and is where cells start migrating inwards to form different layers.
✔ Why is it important?
It marks the beginning of gastrulation, where three germ layers form:
Ectoderm → Skin, nervous system.
Mesoderm → Muscles, bones, heart.
Endoderm → Digestive & respiratory tracts.
✔ How does it relate to the heart?
Some mesodermal cells migrate through the primitive streak to form the cardiac crescent, which later becomes the heart.
Cardiac Crescent
✔ What is it?
The earliest heart-forming region in the embryo (appears around Day 15).
Made up of cardiac progenitor cells that will give rise to the heart tube.
✔ What happens next?
1️⃣ The cardiac crescent merges at the midline to form the linear heart tube (Day 21).
2️⃣ The heart tube loops and folds (Day 28), forming chambers.
3️⃣ The heart matures into a four-chambered organ (Day 50).
✔ Why is it important?
If cells fail to migrate properly, it can lead to congenital heart defects (e.g., heart looping defects).
Neural Crest Cells
✔ What are they?
Neural crest cells are a special group of cells that migrate from the edges of the neural tube [neural tube is the embryonic structure that later forms the brain and spinal cord] and form many different structures.
They come from the ectoderm but behave like mesodermal cells in their migration.
✔ What do they form?
Parts of the heart, especially the outflow tract (aortic and pulmonary arteries).
Parts of the face and skull.
The peripheral nervous system (sensory & autonomic nerves).
Melanocytes (pigment cells in the skin).
✔ Neural Crest & Heart Development
Neural crest cells migrate to the heart and contribute to:
Septum formation (dividing the heart into left and right sides).
The aortic and pulmonary arteries.
Smooth muscle in large blood vessels.
✔ What happens if neural crest cells don’t migrate correctly?
Can lead to congenital heart defects like Tetralogy of Fallot (a combination of four heart abnormalities).
📌 Key Stages in Heart Development
1️⃣ Cardiogenic Specification
The heart forms from mesoderm-derived cells in the primitive streak.
These cells migrate to the cardiac crescent and become heart-forming regions (heart fields).
2️⃣ Folding & Heart Tube Formation
The flat cardiac crescent folds into a tube around Day 18-21.
This linear heart tube will become the heart’s chambers.
3️⃣ Cardiac Looping (Day 23-28)
The heart tube bends and twists to create the basic shape of the heart.
This step is critical for left-right asymmetry in the heart.
4️⃣ Septation (Day 26-35)
Walls (septa) form inside the heart, dividing it into four chambers (atria and ventricles).
Errors in septation can lead to congenital heart defects like atrial septal defect (ASD).
5️⃣ Valve Formation & Trabeculation
Valves form to ensure one-way blood flow.
Trabeculation = muscle ridges that help form the heart’s pumping walls.
6️⃣ Great Vessel Formation (Aorta & Pulmonary Arteries)
The outflow tract (truncus arteriosus) separates into the aorta and pulmonary artery.
This ensures proper circulation between the lungs and the body.
📌 Timeline of Events (Right Side of Image)
Heart tube forms first (~Day 18).
Heart looping follows (~Day 23-28).
Septation, valve formation, and vessel formation happen simultaneously (~Day 26-39).
These processes overlap, meaning they don’t happen in a strict sequence but rather at the same time.
Regulation of Heart Development:
📌 Key Regulatory Mechanisms
✔ Genetics & Epigenetics
Over 500 genes regulate heart development.
No single gene controls heart formation—it’s a complex interaction of multiple genes.
✔ Transcription Factors & Morphogens
Signals like FGF, Wnt, BMP, and Notch guide heart cell differentiation.
These signals act in autocrine (self), paracrine (nearby), and endocrine (distant) ways.
✔ Extracellular Matrix (ECM) & Adhesion
The ECM guides cell movement and provides structural support.
Proteins like fibronectin, integrins, and collagen help shape the heart.
✔ Mechanical Forces & Hemodynamics
Shear forces from blood flow help shape heart valves and vessels.
Cell migration is driven by mechanical cues from ECM and surrounding tissues.
✔ Cell Processes (Fates of Cells in the Heart)
Survival & Proliferation → Cells must multiply to build the heart.
Epithelial-Mesenchymal Transition (EMT) & Migration → Some cells must transition into mobile forms to migrate.
Apoptosis (Cell Death) → Important for refining heart structures (e.g., removing unnecessary tissue for valve formation).
Early Embryonic Development (Days 0-18)
1️⃣ Days 0-6: Formation of the Blastocyst
After fertilization, the zygote undergoes multiple cell divisions.
By Day 5, it becomes a blastocyst (a hollow ball of cells).
The blastocyst consists of:
Trophoblast → Forms the placenta.
Inner Cell Mass → Forms the embryo.
2️⃣ Days 7-12: Bilaminar Embryo (2 Layers)
The inner cell mass forms two layers, called the bilaminar embryonic disc:
Epiblast → Becomes the baby!
Hypoblast → Forms extra-embryonic structures (e.g., yolk sac).
The embryo fully implants into the uterus during this time.
3️⃣ Days 13-18: Gastrulation (Trilaminar Embryo, 3 Layers)
Yes! The epiblast is the ONLY layer that forms the three germ layers during gastrulation.
1️⃣ The epiblast moves toward the midline, forming a thickened line called the primitive streak.
2️⃣ Epiblast cells migrate inward through the primitive streak and form:
Mesoderm (middle layer).
Endoderm (inner layer).
3️⃣ The remaining epiblast cells stay on top and become ectoderm (outer layer).
2️⃣ What Happens to the Hypoblast?
The hypoblast does NOT form the three germ layers—instead, it gets replaced by the endoderm.
As epiblast cells migrate inward, they push the hypoblast cells out of the way.
The new endoderm cells (from the epiblast) replace the hypoblast.
The hypoblast mostly contributes to extra-embryonic structures, like the yolk sac.
💡 So, the hypoblast is temporary—it does NOT form the embryo!
Gastrulation & Mesoderm Subdivisions
📌 Key Concepts
1️⃣ Gastrulation & 3 Germ Layers
Ectoderm → Forms the neural tube & skin.
Mesoderm → Forms muscles, bones, heart, kidneys.
Endoderm → Forms the gut, lungs, and liver.
2️⃣ Mesoderm Further Subdivides
After the mesoderm forms, it splits into different regions:
- Paraxial Mesoderm → Forms somites, which become bones, muscles, and dermis (skin layer).
- Intermediate Mesoderm → Forms the kidneys and gonads.
- Lateral Plate Mesoderm (Important for the heart!):
Somatic (body wall) mesoderm → Forms body structures (e.g., ribs).
Splanchnic (organ) mesoderm → Forms the heart, blood vessels, and gut walls.
💡 The lateral plate mesoderm is where the heart forms!
How is the Primitive Streak a Pathway for Cells to Create the Three Germ Layers?
Yes! The primitive streak is NOT one of the germ layers itself—it is just the gateway that allows epiblast cells to migrate and form the layers.
1️⃣ Epiblast cells move toward the primitive streak.
2️⃣ They dive down through it → This is how cells move to their new positions.
3️⃣ As they move through, some spread out to form mesoderm and endoderm.
So the primitive streak is like a tunnel or doorway—cells go through it, then spread out into different layers.
💡 Without the primitive streak, the epiblast cells wouldn’t know where to go to form the mesoderm and endoderm!
Cardiogenic Mesoderm?
Epiblast Cells Migrate Through the Primitive Streak
Some epiblast cells move inward through the primitive streak.
These migrating cells differentiate into mesoderm (the middle germ layer).
Mesoderm Spreads and Moves Cranially (Towards the Head)
Some mesodermal cells migrate forward (cranially), ending up in front of the developing brain.
This group of mesodermal cells is called the cardiogenic mesoderm.
It sits in the splanchnic mesoderm (a part of mesoderm that will form internal organs).
This mesoderm is the earliest stage of heart development.
Over time, it will form two patches of tissue called the first and second heart fields.
These fields will merge at the midline and form the heart tube, which will later fold and develop into a four-chambered heart.
Heart Fields?
Heart fields refer to specific regions of the cardiogenic mesoderm that give rise to different parts of the heart. There are two main heart fields:
First Heart Field (FHF)
Forms early heart structures, including:
Left atrium
Left ventricle
This is the earliest part of heart development.
Second Heart Field (SHF)
Forms later structures, including:
Right ventricle
Outflow tract (aorta and pulmonary artery)
This field is located medial (closer to the center) than the first heart field.
These fields come from cardiogenic mesoderm, which migrated from the primitive streak and settled in the cranial region.
What Are Morphogens
Morphogens are chemical signals that control how cells differentiate (turn into specific cell types). They work by forming gradients, meaning different concentrations of the signal tell different cells what to become.
BMP2, BMP4, TGFβ, Activin → Promote heart cell formation
Wnt1/3a/8a (from neural tube) → Inhibit heart development (must be blocked)
Crescent (FRZB2), Dickkopf (DKK1) → Block Wnt signals, allowing heart development
A gradient means that different areas of the embryo have different levels of these morphogens.
Cells near HIGH BMP/TGFβ levels → Will differentiate into heart cells.
Cells near HIGH Wnt levels → Will not form heart tissue.
Crescent & DKK1 BLOCK Wnt → This allows heart tissue to form in the correct place.
So yes, morphogen gradients create zones where cells receive different instructions based on the concentration of signals they are exposed to.
Left-Right (L-R) Specification
The heart needs to be asymmetrical, meaning that the left side and right side are different.
Key signals for left-right asymmetry:
Left Side: Sonic Hedgehog (SHH) activates Nodal → Pitx2, which promotes left-sided development.
Right Side: Activin signaling represses SHH and promotes FGF8, leading to right-sided development.
This ensures proper looping of the heart later in development.
SHH and activin, morphogens, SHH → Nodal → Pitx2 ensures the heart, stomach, and other organs develop on the left.
Activin → FGF8 represses SHH on the right, ensuring asymmetry.
Heart Tube Formation and Folding (Days 20-21)
The cardiogenic mesoderm forms two heart fields (left and right).
Lateral folding brings these two heart fields together at the midline, where they fuse into a single heart tube.
Blood flow begins on Day 22, where the heart tube starts peristaltic contractions to circulate early blood.
Further Development (Days 22-28)
Heart tube fusion happens cranial to caudal (head to tail).
Heart tube starts beating on Day 24.
Looping (Day 28): The heart tube bends and twists to form primitive chambers (atria, ventricles).
Heart Tube Fusion and Looping
Heart Tube Fusion and Looping
🔹 Lateral folding (Day 22):
The heart tubes fuse from cranial to caudal.
The myocardium (heart muscle) starts forming.
The inner cells become endocardium.
Cardiac jelly (a gel-like matrix) forms to help structure the heart.
🔹 Looping (Days 24-28):
The straight heart tube bends and twists into an S-shape.
The left ventricle moves downward and right.
The sinus venosus (veins) moves backward.
This process ensures proper chamber alignment.
📍 Why is looping important?
It ensures the atria and ventricles are in the correct position for blood flow.
Heart Looping: A Step-by-Step Breakdown
Step 1: Formation of the Primitive Heart Tube (Day 21-22)
🔹 The splanchnic mesoderm differentiates into two heart fields (first and second heart fields).
🔹 Cells from these heart fields migrate and fuse at the midline during lateral folding, forming the primitive heart tube (a straight tube at first).
🔹 Blood flow starts around day 22 with a peristaltic wave motion.
📌 Key structures in the primitive heart tube (from caudal to cranial, i.e., bottom to top):
Sinus Venosus (SV) → will form part of the right atrium and great veins.
Primitive Atrium → will give rise to both left and right atria.
Primitive Ventricle → forms the left ventricle.
Bulbus Cordis (Conus) → contributes to the right ventricle and outflow tracts.
Truncus Arteriosus → forms the ascending aorta and pulmonary artery.
Aortic Sac → contributes to aortic arches.
🚨 At this stage, the heart tube is still straight! Now looping begins.
Step 2: Rightward (D-Looping) - Day 23-28
🔹 The heart tube elongates and bends due to differential growth and forces from surrounding tissues.
🔹 The bending occurs in an S-shape (dextro-looping or D-looping):
The primitive ventricle moves caudally (down) and left.
The bulbus cordis (future right ventricle) moves ventrally (forward) and to the right.
The atrium and sinus venosus move dorsally (backward) and cranially (upward).
📌 Why does this happen?
The heart is growing inside the pericardial cavity, but the cavity is too small to contain the expanding tube.
Forces from the surrounding tissue cause the heart tube to twist and bend into a rightward loop.
Step 3: Chamber Specification and Segmentation (Day 28+)
🔹 As the looping progresses, the different regions of the tube expand and form the future chambers:
The primitive atrium splits into left and right atria.
The primitive ventricle gives rise to the left ventricle.
The bulbus cordis (conus) contributes to the right ventricle and outflow tract.
The truncus arteriosus will separate into the aorta and pulmonary trunk.
🔹 Key molecular regulators of looping (from your slides):
Tbx5 → Specifies the atria and sinus venosus.
Irx4 → Specifies the ventricles and outflow tract.
Retinoic acid → Helps define atrial regions.
Epithelial-Mesenchymal Transition (EMT) → Cells migrate from the second heart field, helping in chamber expansion.
Step 4: Final Adjustments and Septation (Day 35+)
🔹 The heart has now formed an S-shaped structure.
🔹 Over the next few weeks, septation (wall formation) begins:
The atrioventricular canal forms the mitral and tricuspid valves.
The truncus arteriosus separates into the aorta and pulmonary artery.
The interventricular septum grows, separating the left and right ventricles.
Regulators of Heart Looping:
- Tbx5 – Specifies the Atria and Sinus Venosus
🔹 What is it?
Tbx5 (T-box transcription factor 5) is a gene that encodes a transcription factor, meaning it controls the expression of other genes.
🔹 Role in Looping & Heart Development:
Expressed in the atria and sinus venosus.
Helps in defining left and right atrial identity.
Works with Nkx2.5 (another key cardiac gene) to coordinate atrial development.
Mutations in Tbx5 cause Holt-Oram Syndrome, which leads to congenital heart defects and limb abnormalities.
2. Irx4 – Specifies the Ventricles and Outflow Tract
🔹 What is it?
Irx4 (Iroquois homeobox gene 4) is a transcription factor that regulates genes involved in ventricular formation.
🔹 Role in Looping & Heart Development:
Specifies ventricular identity—helps cells differentiate into ventricular myocardium.
Expressed mainly in the ventricles and outflow tract (OFT) (bulbus cordis and truncus arteriosus).
Works with Nkx2.5 and Hand1 to define ventricular structure.
Without Irx4, ventricles develop abnormally, leading to malformation of the outflow tract.
3. Retinoic Acid – Helps Define Atrial Regions
🔹 What is it?
Retinoic acid is a derivative of Vitamin A that acts as a signaling molecule in embryonic development.
🔹 Role in Looping & Heart Development:
Regulates atrial development by influencing gene expression.
Helps to form atria and sinus venosus—without retinoic acid, these regions fail to develop properly.
The enzyme Raldh2 (retinaldehyde dehydrogenase 2) is crucial for retinoic acid production and is expressed caudally (towards the tail end) to establish the atrial boundary.
Too much or too little retinoic acid can cause congenital heart defects, including atrial and ventricular malformations.
4. Epithelial-Mesenchymal Transition (EMT) – Cell Migration from the 2nd Heart Field
🔹 What is it?
EMT is a biological process where epithelial cells lose adhesion and become migratory mesenchymal cells.
🔹 Role in Looping & Heart Development:
Cells from the second heart field (SHF) undergo EMT to migrate and contribute to cardiac looping and chamber formation.
EMT is regulated by genes like Snail, Twist, and BMPs.
Essential for outflow tract formation, valve development, and septation.
Disruptions in EMT lead to heart defects like valve malformations.
How These Regulators Work Together in Heart Looping
Tbx5 → Specifies atria and sinus venosus, helping in early looping.
Irx4 → Specifies ventricles and outflow tract, guiding the formation of major pumping chambers.
Retinoic Acid → Helps in atria development and ensures proper chamber organization.
EMT → Enables cells to migrate from the second heart field, helping in heart expansion and septation.
These regulators work together in a highly coordinated manner to ensure the heart loops correctly, forming the four-chambered heart.
Septation: How the Heart Gets 4 Chambers
The primitive heart starts as one chamber.
How does it divide?
Atrial septation
Septum primum grows downward [a tissue structure that grows between the left and right atria of the heart during fetal development]
Foramen ovale allows blood to bypass lungs in the fetus.
Ventricular septation
The muscular ventricular septum [ventricular septum is the wall that separates the left and right ventricles] forms first.
The membranous ventricular septum completes the separation.
💡 What happens if septation fails?
Atrial septal defect (ASD) → Hole between atria
Ventricular septal defect (VSD) → Hole between ventricles
——————————————–
1. Atrial Septation (Separating Left and Right Atria)
🔹 Septum Primum forms
A thin, flexible wall grows downward from the roof of the atrium.
It starts closing the gap between the left and right atria.
🔹 Foramen Primum (Temporary Opening)
Before the septum fully closes, an opening (foramen primum) remains, allowing blood to bypass the lungs.
🔹 Foramen Secundum forms
Before the foramen primum closes, a new set of holes (foramen secundum) appear in the septum primum.
This ensures that blood can still flow from right to left atrium.
🔹 Septum Secundum grows next to it
A thicker, more rigid septum (septum secundum) grows beside the septum primum.
It partially covers the foramen secundum, leaving a flap-like opening called the foramen ovale.
🔹 Post-birth closure
After birth, when the baby starts breathing, pressure in the left atrium increases, and the foramen ovale closes.
- Ventricular Septation (Separating Left and Right Ventricles)
🔹 Muscular Septum forms first
The lower portion of the ventricles grows a muscular wall upward.
🔹 Membranous Septum closes the gap
The final gap at the top is closed by cells from the endocardial cushions.
These cushions are formed via EMT (epithelial-mesenchymal transition).
🔹 Ventricular Septal Defects (VSD)
if the membranous septum fails to form, a hole remains between the ventricles, causing a congenital defect. - Outflow Tract Septation (Separating Aorta & Pulmonary Artery)
🔹 Neural crest cells migrate
Neural crest cells form two spiraling ridges inside the outflow tract [pulmonary artery and aorta].
🔹 These ridges fuse
They form a spiral septum that twists as it divides the outflow tract.
=> ensures the aorta connects to the left ventricle and the pulmonary artery connects to the right ventricle.
What Happens If This Process Fails?
Persistent Truncus Arteriosus → Aorta & Pulmonary artery fail to separate, one common vessel instead of two.
==> oxygenated and deoxygenated blood to mix, leading to severe heart problems.
Transposition of Great Vessels → Aorta & Pulmonary artery switch places.
==>no proper oxygenation of blood,
Cardiac Jelly & EMT (Epithelial-Mesenchymal Transition)
Cardiac jelly is a gelatinous extracellular matrix secreted by heart cells.
It provides a scaffold for cells to migrate and helps in early heart development.
==> endocardium (inner heart lining) to migrate and form endocardial cushions.
–> These cushions later contribute to the formation of heart valves and septa.
EMT
===> is a process where epithelial cells (tightly packed cells) transform into mesenchymal cells (mobile cells that can migrate)
allows cells to invade the cardiac jelly and build structures like heart septa and valves.
==> Once cells undergo EMT, they need a place to migrate into.
Cardiac jelly acts like a soft, scaffold-like cushion where transformed cells can move, spread, and invade.
–> Think of EMT as unlocking the ability to move, while cardiac jelly is like the pathway that guides them.
It provides chemical and physical signals that allow cells to reach the right location and form the endocardial cushions.
Why is This Important?
✅ Cardiac jelly provides a supportive environment for cells to migrate.
✅ EMT enables cell migration and invasion into the cardiac jelly.
✅ Endocardial cushions form, which later develop into valves and septa.
