Heart Muscle _ Heart development - Heart Muscle Differentiation

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					Heart Muscle
Differentiation
  Heart Muscle Differentiation
THE HEART
• Structure and function
• Anatomy of the heart


HEART DEVELOPMENT
• Overview of Heart Formation
• Genetic factors regulating cardiac
  muscle differentiation


WHAT HAPPENS WHEN IT ALL GOES WRONG?
• Congenital Heart Disease
WHAT ARE THE REQUIREMENTS
       OF A PUMP???
1. Receiving Chambers
       Left and Right
            Atria

2. Delivery Chambers

       Left and Right
         Ventricles
   WHAT ARE THE REQUIREMENTS
          OF A PUMP???
     3. Valves to direct the flow of blood

pulmonary
  Valve                                 Aortic
                                        Valve


tricuspid                                Mitral/
 Valve                               Bicuspid Valve
WHAT ARE THE REQUIREMENTS OF A PUMP?
 4. Strongly contractile wall to provide the force
             required to propel blood




                                           Nucleus
                            Intercalated
                            Disc
      CARDIAC MUSCLE
           CELLS
•Cardiomyocytes
                                                         Nucleus
• contractile element of cardiac muscle   Intercalated
                                          Disc
• elongated cells

• centrally located nucleus

• branched cells

• separated from each other by the
  presence of intercalated discs

• filled with rod-like bundles of
  myofibrils (contractile proteins s.a.
  myosin and Actin)
THE 6 REQUIREMENTS OF A PUMP

1. Receiving chambers
2. Delivery chambers
3. Valves to direct the flow of blood
4. Strong contractile wall to propel blood

5. Vessels to deliver blood
6. Conduction system to regulate the pump
 5. Vessels to Deliver Blood
 6. Conduction System



                                                                  AORTA
 SUPERIOR                  ASCENDING AORTA
 VENA CAVA                                                          PULMONARY ARTERY

                                LEFT
                                ATRIUM                                    LEFT ATRIUM
                                     SA NODE

                                    AV NODE                               MITRAL VALVE
RIGHT
ATRIUM                                  RIGHT                             AORTIC
                                        ATRIUM                            VALVE
                                                                          PULMONARY VALVE

                                                                              RIGHT VENTRICLE


INFERIOR                                TRICUSPID
VENA CAVA                               VALVE                             INTERVENTRICULAR
                                                                           SEPTUM
                                                 LEFT VENTRICLE

             LEFT ANTERIOR DESCENDING                     CONDUCTION SYSTEM
             CORONARY ARTERY
            HEART FORMATION

• Gastrulation - formation of 3
  germ layers

       • ENDODERM
       • ECTODERM
       • MESODERM

• Heart is derived from the
  mesoderm

• First indication of human heart
  development is around day 16-19
• How do we progress from a single layer of
  mesoderm to the complex 3 dimensional
  structure of the heart???
differentiation
    • Genes




Morphogenesis

• Process of Heart
     Formation
Cardiogenic Mesoderm




             Cardiac
             Cresent

             Cardiac
            Progenitor
               cells)
              HEART FORMATION
1. Formation of endocardial   2. Formation of the Primitive
   tubes derived from            heart tube
   mesodermal cells




                                                   Fusing
                                                   Heart
                                                   tubes

         Day 18                     Day 22


        Endothelial             Primative/linear
    (endocardial) Tubes            Heart Tube
             HEART FORMATION
3. Primitive heart tube develops into 5 distinct regions

                                             Truncus
                                             Arteriosus

                                              Bulbus
                                              Cordis

                  Fusing
                  Heart                       Ventricle
                  tubes

                Day 22
                            Atrium     Sinus Venosus
              HEART FORMATION
             4. Primitive heart tube Twists


                    Truncus Arteriosus

                      Bulbus Cordis



                      Ventricle
Day 23
                         Atrium
                         Sinus
                         Venosus



 Looping brings the distinct regions of the heart into the
    basic pattern that prefigures the adult structure
                  HEART FORMATION
The bulbus cordis and truncus arteriosus have divided into two
       vessels forming the aorta and pulmonary trunk

         Superior                              Aorta
         vena cava
                                               Pulmonary
                                                 Trunk

                                               Atrium



                                                Ventricle
         Inferior
        Vena cava

    Week 7 - the interatrial and interventricular septa have formed
    partitioning the atria and ventricles into L and R compartments
                    Mouse Heart Formation
Cardiac crescent                                         Intra-embryonic coelom
      stage                                              Heart progenitors
     (E7.75)



Linear heart tube                                        Myocardium

     (E8.0)                                              Endocardium
                                                         Conotruncal cushions
                                                         Endocardial cushions
 Looping heart
                                 RV
                                           LV
    (E10.5)                                          Inter-ventricular septum
                                                           Trabeculae

                                                         Atrial septum
                                  RA            LA
Remodelling heart                                        Endocardial cushions
    (E12.5)                           RV        LV       Inter-ventricular septum

                                                         Trabeculae
   Early identification of Cardiac Progenitors
           in Mouse Embryo Day 7/7.5

                                          Neural Plate

                                                 Ectoderm


             Cardiac
             Cresent

             Cardiac                Head
            Progenitor             Mesoderm
                                               Cardiac
               cells)                         Mesoderm

    E7.75

Whole mouse embryo          Transverse section
Heart Development in the Mouse




                       J.M. Icardo, 1997
       AT WHAT STAGE DOES THE
        HEART START PUMPING?

• Human primitive heart begins contracting at day 22

• Mouse heart starts to contract around day 8

• Why does the heart start to contract so early???
GENETIC CONTROL OF HEART MUSCLE
      CELL DIFFERENTIATION
• Genetic dissection of heart (dorsal vessel) formation in
  Drosophila has led to the identification of a number of
  genes implicated in heart determination

     tw                                         Dhand
       is t




                                                     pe
                                                      i
                                                   gp
 tinman




                                                 ba
                                                   Dm ef2
       p
     dp
What does tinman do?
                • homeobox gene

                • identified in 1989 by
                  Kim and Nirenberg

                • localised to the
                  dorsal mesoderm

                • later stages to
                  heart precursors
                  and mesoderm

                • Does tinman play a
                  role in heart
                  formation?
Does tinman play a role in
   heart development?

           • Disco - identify cardial cells of the
             dorsal vessel

           • visceral mesoderm expression in
             wt embryos

           • tinman k/o - no heart or visceral
             mesoderm formation

           • tinman expression is crucial for
             heart formation in drosophila
TRANSCRIPTIONAL CASCADE FOR
CARDIOGENESIS IN DROSOPHILA
                       TWIST

                                               Ventral
      tinman                           D-mef2 mesoderm
    Dpp       Wg

                    Cells committed            Dorsal
      tinman
                 to a cardiogenic fate        mesoderm

                       Activation of
      D-mef2           transcription
                                                Heart
                                              Precursors

Contractile protein genes
• twist is essential for mesoderm
  formation

• 6 different genes related to tinman
  were isolated from divergent
  species
      Nkx2-3
      Nkx2-5 (1993 Kamuro and Izumo,
               Harvey 1996)
      Nkx2-6
      Nkx2-7
      Nkx2-8
      Nkx2-9

• evolutionary conservation

• Does Nkx2-5 have a similar
 function to tinman?
   Localisation of Nkx2.5 positive cells in the
developing mouse embryo using Lac Z Expression




                               Cardiac
                               Cresent

                                Cardiac
                               Progenitor
                                  cells)




                                            E7.75
• Nkx2-5 expressed in the
  mesoderm

• later stages it is only
  expressed in the heart

• panel E shows no expression
  of Nkx2-5 in the lungs

• k/o Nkx2.5 there is no effect
  on early heart formation

•   looping/twisting
    morphogenesis is
    affected
Muscle   Peri-cardial   VM
    Expression of Cardiac NK2-class Homeobox genes

 tinman Drosophila                    Frog Nkx2-5




          Mouse




Nkx2-5
           Chick




         Zebrafish
  GENETIC CONTROL OF HEART MUSCLE
        CELL DIFFERENTIATION

• Nkx2 class hoemobox genes are expressed during
  gastrulation in the lateral plate mesoderm
  (mouse, frog, avian and fish embryos)

• critical determinants of cardiac development

• Studies in Drosophila have shown tinman expression
  to be essential for heart development

• Absence of Nkx2-5 in the mouse doesn’t prevent the
  formation of the heart tube but blocks looping
  and septum formation
CONSERVATION OF GENETIC PATHWAYS
      IN HEART DEVELOPMENT
   CONSERVATION OF THE GENETIC PATHWAYS
           IN HEART DEVELOPMENT
              Congenital Heart Disease
 • Defects present from birth

 • affect <1 % of all children

 • Morphogenesis of the heart has many stages
Pulsating   Twisting/rotating   Septa Formation   4 Chamber
  tube            heart                              Organ


 • Ample opportunity for something to go wrong

 • Not surprising that abnormalities occur, perhaps
   more surprising that the occurrence of abnormality
   is so infrequent.
          Congenital Heart Disease

• What kind of abnormalities occur????

• Incomplete septa formation (holes between chambers)
• Incorrect connection between chambers and vessels
• valves that don’t function properly

• Atrial septal defect
• ventricular septal defect
• Tetralogy of Fallot
             Atrial Septal Defect




• incomplete closure between 2 upper chambers
• Blood returning from lungs flows through the hole
• More blood flows through R side of heart
• pulmonary hypertension
• in most cases surgery can rectify this problem
      Ventricular Septal Defect




• incomplete closure between 2 ventricles
• Initially blood flows from R to L
• heart dilates, pressure increases resulting in
  pulmonary hypertension due to increased workload
• in most cases spontaneous closure occurs
•If needed surgery can rectify this problem
             Tetralogy of Fallot




1. Ventricular septal defect
2. Pulmonary stenosis (narrowing of pulmonary artery)
3. Hypertrophy (thickening of the RV wall)
4. Overriding aorta
Decreased blood flow to the lungs and mixing of blood
    Nkx2-5 and Human Cardiac defects

• Recent investigations have mapped a mutation
  causing atrial septal defects to the NKX2-5 gene
  (Schott et al 1998)

• Decreased capacity of this transcription factor to
  bind DNA

• implicates Nkx2-5 in atrial septation and
  conduction system development
More recent reviews
Buckingham et al 2005 Building The Mammalian Heart From
Two Sources Of Myocardial Cells Nature reviews –genetics
6:826-835
Srivastava 2006 Making or Breaking the Heart: From
Lineage Determination to Morphogenesis Cell 126:1037-1048
NKX2-5 in ventricular muscle – Srivastava Nature 2004

				
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