jigjiga UNIVERSITY

histology

FOR MEDICINE STUDENTS

 Reference

• Anthony L. Mesche, Junqueira’s Basic

Histology, Text And Atlas, 13th Edition
• Michael H. Ross, Histology a Text And Atlas
With Correlated Cell And Molecular Biology,
6th Edition
• Barbara Young, Wheater’s Functional
Histology, A Text And Colour Atlas, 6 Edition

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 CELL
• Cell is the basic living structural and functional unit of
the body.
• There are two fundamentally different types of cells
1. Prokaryotic (Gr. pro, before, + karyon, nucleus) cells
• Found only in bacteria.
• These cells are small (1–5µm long)
• Typically have a cell wall outside the plasmalemma
• Lack a nuclear envelope.
• Have no histones (specific basic proteins) bound to
their DNA and
• Usually no membranous organelles.

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 Cell cont...
2. Eukaryotic (Gr. eu, good, + karyon, nucleus) cells
• Are larger
• Have a nucleus surrounded by a nuclear envelope.
• Histones are associated with the genetic material, and
• Numerous membrane-limited organelles are found in
the cytoplasm.

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 Cell cont...

─ Our discussion focus exclusively on eukaryotic

cells
Human cells have three main parts:
• The plasma membrane,
• The cytoplasm, and
• The nucleus

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 Plasma Membrane
• It is also called plasmalemma is a thin outer
membrane, which maintains the integrity of the cell.
• It keeps the cell and its contents separate and distinct
from the surrounding.
• The plasma membrane is composed of an
amphipathic lipid layer containing embedded
integral membrane proteins with peripheral
membrane proteins attached to its surfaces
• It is a double layered measuring about 7.5- 10nm in
diameter
• The bi-layer is self-sealing.
• If a needle is injected and pulled out, it automatically
seals. 7
 Structure of plasma membrane
According to the fluid mosaic model
• The plasma membrane made of:
1. Lipids: The most abundant lipids in the plasma
membrane are phospholipids.
• Each phospholipid molecule has a polar “head”
that is charged, and an uncharged nonpolar
“tail” made of two chains of fatty acids.

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 Structure cont…
• The polar heads are attracted to water and lie
along the inner as well as the outer face of the
membrane.
• The nonpolar tails avoid water and line up in the
center of the membrane.
• The plasma membrane also contains substantial
amounts of cholesterol.
• Cholesterol makes the membrane more rigid
and increases its impermeability to water and
water-soluble molecules.
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2. Proteins
• Proteins make up about half of the plasma
membrane by weight.
• The membrane proteins are of two distinct
types: integral and peripheral.
• Integral proteins are firmly embedded in or
strongly attached to the lipid bilayer.
• Peripheral proteins, by contrast are not
embedded in the lipid bilayer at all.
• Instead, they attach rather loosely to the
membrane surface.
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 Proteins cont…
• Six broad categories of membrane proteins
have been defined in terms of their function:
─pumps, channels, receptors, linkers, enzymes,
and structural proteins.
─The categories are not mutually exclusive (e.g., a
structural membrane protein may simultaneously
serve as a receptor, an enzyme, a pump, or any
combination of these functions).

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 Proteins cont…
Pumps: serve to transport certain ions, such as
Na+, actively across membranes.
Pumps also transport metabolic precursors
of macromolecules, such as amino acids and
sugars across membranes either by themselves or
linked to the Na+ pump

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 Proteins cont…
Channels: allow the passage of small ions,
molecules, and water across the plasma
membrane in either direction (i.e. passive
diffusion).
– Gap junctions formed permit passage of
ions and small molecules from the cytoplasm of
one cell to the cytoplasm of the adjacent cells

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 Proteins cont…
Receptor proteins: allow recognition and
localized binding of ligands (molecules that bind
to the extracellular surface of the plasma
membrane) in processes such as hormonal
stimulation, coated-vesicle endocytosis, and
antibody reactions.
Linker proteins: anchor the intracellular
cytoskeleton to the extracellular matrix.
▪ Examples of linker proteins include the family of
integrins that link cytoplasmic actin filaments to
an extracellular matrix protein (fibronectin).

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 Proteins cont…
•Enzymes have a variety of roles.
❖ ATPases have specific roles in ion pumping:
❖ ATP synthase is the major protein of the inner
mitochondrial membrane, and
❖ Digestive enzymes such as disaccharidases and
dipeptidases are integral membrane proteins
Structural proteins are visualized by the freeze
fracture method, especially where they form
junctions with neighboring cells.

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Different functions of integral membrane proteins. The
six major categories of integral membrane proteins are
shown in this diagram: pumps, channels, receptors,
linkers, enzymes, and structural proteins.
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Freeze fracture
examination of the
plasma membrane

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3. Carbohydrates
• Short chains of carbohydrate molecules attach to
the integral proteins to form glycoproteins or to
lipid bilayer forming glycolipid.
• These sugars project from the external cell
surface, forming the glycocalyx.

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Glycocalyx
• Sugar coat in outer leaflet, thickness = 50nm.
• Consists of polar oligosaccharide side Chains linked
covalently to most protein & some lipid (glycolipid).
• Consists cell-surface proteoglycans to which are bound
glycosaminoglycans.
Function of glycocalyx
– Help cells to bind when they come together.
– Help as a binding of antigens & enzymes to the cell
surface.
– Facilitate cell-cell recognition & interaction (e.g.,
sperm – egg adhesion).
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 Functions of plasma membrane
1. Separate the cytoplasm inside a cell from extra
cellular fluid.
2. Separate cell from one another
3. Act as receptors
4. Provide an abundant surface on which chemical
reaction can occur.
5. Regulate the passage of materials into and out
of cells.

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 Movement across-cell membrane
• Movements a cross membrane takes place in two
ways. These are:
❖Passive process and
❖Active process
• Passive movement do not consume energy whereas
active movement consumes energy in the form of ATP.

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 Passive process

It includes:

a. Simple diffusion, the random movements of molecules

from area of high concentration to the area of low
concentration.

E.g. Small, uncharged (nonpolar) molecules, such as

oxygen, carbon dioxide, and fat-soluble molecules

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 Passive movement cont…

b. Facilitated diffusion, most water-soluble or charged

(polar) molecules, such as glucose, amino acids, and
ions, which are not soluble in lipid need channel &
carrier protein to pass through the plasma membrane.

• These molecules move down their concentration

gradient.

• No direct energy needed.

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Channel-mediated: Movement of ion down its
concentration gradient through a protein channel
Na+ moves through Na+ channel into cell
Carrier-mediated: Movement of small, polar
molecule down its concentration gradient by a
carrier protein
Transport of glucose into cells by glucose carrier

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 Passive movement cont…

c. Osmosis: a special type of diffusion referring to the

passage of water through a selectively permeable
membrane from an area of high water concentration
to lower water concentration.
• Transmembrane diffusion of water molecules
(by osmosis) involves their passive movement
through multi-pass transmembrane proteins called
aquaporin's

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 Active process

• Movement of substances requires expenditure

of cellular energy
a. Active transport
• Transport of ions or small molecules across the
membrane against a concentration gradient by
transmembrane protein pumps.
• This is against concentration gradient.
• Therefore, it requires energy.

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 a. Active Transport cont…
For Examples
• Ca2+ pumps: transport Ca2+ out of the cell
• Na+/K+ pump; moves Na+ out of cell and K+ into
cell.
❖Movement of substance up its concentration
gradient; powered directly by ATP
• Na+/glucose transport: Movement of substance up its
concentration gradient in the same direction as Na+.
• Na+/H+ transport: Movement of substance up its
concentration gradient in the opposite direction from
Na+

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b. Vesicular or bulk transport.
The largest molecules (macromolecules) and large solid
particles are transported through the plasma membrane by
another set of processes, called vesicular or bulk
transport.
•There are two general types of bulk transport, exocytosis
and endocytosis.
Endocytosis (“into the cell”) is the mechanism by which
large particles and macromolecules enter cells.
Three types of endocytosis are recognized:
✓Phagocytosis
✓Pinocytosis, and
✓Receptor-mediated endocytosis.

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Phagocytosis; is literally “cell
eating.”
•Involves the extension from the
cell of large folds called
pseudopodia that engulf particles,
for example bacteria, and then
internalize this material into a
cytoplasmic vacuole or
phagosome.
•E.g., white blood cells

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Pinocytosis; is literally “cell
drinking.”
•The cell membrane invaginates
(dimples inward) to form a pit
containing a drop of extracellular fluid.
•The pit pinches off inside the cell
when the cell membrane fuses and
forms a pinocytotic vesicle containing
the fluid.
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Receptor-mediated endocytosis; some molecules, such
as insulin and other hormones, enzymes, and low-
density lipoproteins (LDLs) are brought into cells
through receptor-mediated endocytosis.
•These substances bind to specific receptors on the cell
membrane.
•Upon binding, the portion of the plasma membrane
bearing the molecules and attached receptors
invaginates and is pinched off, bringing into the cell the
membrane-bound vesicle containing the molecules.

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 Major steps during and after endocytosis
• Ligands bind at high affinity to specific surface
receptors.
• Then, associate with specific cytoplasmic proteins,
including clathrin and adaptor proteins, and form
coated pits.
• Clathrin facilitates invagination of the pits, and
• Dynamin, forms constricting loops around the
developing neck of the pit, which cause the region to
pinch off as a coated vesicle.

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 Major steps endocytosis cont…
• The internalized vesicles lose their clathrin coats and
usually merge by membrane fusion with other
endosomal vesicles.
• Ligands may have different fates within the endosomal
compartment:
■ Receptors and ligands may be carried to late
endosomes and then to lysosomes for degradation.
■ Ligands may be released internally and the
receptors recycled to the cell surface.
■ Vesicles may move to and fuse with another cell
surface, where the ligands are released again outside
the cell (transcytosis).
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Exocytosis (“out of the cell”) is a mechanism by which
substances move from the cytoplasm to the outside of
the cell.

•Exocytosis accounts for most secretion processes, such

as the release of mucus or protein hormones from the
gland cells of the body.

•In exocytosis, the substance or cell product to be

released from the cell is first enclosed in a membrane-
bound vesicle in the cytoplasm and released into the
space outside the cell.

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 Cytoplasm
• Cytoplasm, literally “cell-forming material,”
is the part of the cell that lies internal to the
plasma membrane and external to the nucleus.
• It consists of three major elements:
Cytosol (cytoplasmic matrix)
Organelles and
Inclusions.

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 Cytosol
• The cytosol, is the jellylike, fluid-containing substance
within which the other cytoplasmic elements are
suspended.
• Cytosol also contains hundreds of enzymes, such as
those of the glycolytic pathway, that produce building
blocks for larger molecules and break down small
molecules to liberate energy.

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 Cytosol cont…
• All the machinery converging on the ribosomes for
protein synthesis (mRNA, transfer RNA, enzymes, and
other factors) is also contained within the cytosol.
• Oxygen, CO2, electrolytic ions, low-molecular-weight
substrates, metabolites, and waste products all diffuse
through cytosol, either freely or bound to proteins.
• In many cell types, the cytosol makes up about half the
volume of the cytoplasm.

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 Cytoplasmic Organelles
Typically, the cytoplasm contains about nine types of
organelles.
Membrane bounded
– Mitochondria
– Rough and Smooth endoplasmic reticulum
– Golgi apparatus
– Lysosomes
– Peroxisomes
Non-membrane bounded
– Ribosomes
– The cytoskeleton and
– Centrioles
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 Ribosomes
• 12-nm wide & 25 nm long
• Composed of rRNA & proteins
• Cluster along single strand of mRNA to form
polyribosomes
• Sites of where mRNA is translated into proteins
• Consists roughly of 60% RNA & 40% protein
(small mRNA, tRNA & large subunits of AA
polypeptide chains – ribonucleoproteins)

45
 Ribosomes cont…
• Intensely basophilic because of the numerous
phosphate groups of the constituent RNAs that act as
polyanions.
• Unlike most organelles, they are not surrounded by a
membrane.
• Ribosomes are the site of protein synthesis.
There are two types of ribosomes
Free ribosomes: make the soluble proteins that function
within the cytosol
Attached ribosomes with RER: Make proteins that
become part of the cell membrane or that are exported out
of the cell.
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 Endoplasmic Reticulum
• The endoplasmic reticulum (ER) is literally the
“network within the cytoplasm.”
• The ER is an extensive system of membrane-walled
envelopes and tubes that twists through the cytoplasm.
• Extends from the surface of the nucleus
to the cell membrane & encloses a series of
intercommunicating channels and sacs called cisternae
• Cisternae collects newly synthesized proteins for
modification and delivery into pathways
leading to other organelles and for secretion.
• There are two distinct types of ER: rough ER and
smooth ER.
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 Rough Endoplasmic Reticulum
• Site where noncytosolic proteins are synthesized
(secretory & lysosomal proteins & plasma membrane).
• System of sacs bounded by membranes (outer surface
studded with ribosomes, interior region called
cisterna).
• Membranes may be continuous with outer nuclear
membranes (peinuclear cisterna).

48
 RER cont…
• Abundant in cells synthesizing secretory
proteins such as:
– Pancreatic acinar cells (digestive enzymes)
– Plasma cells (immunoglobulins)
– Fibroblasts (collagen)
• Has receptors (ribophorins) to which large
ribosomal subunits bind: Hence, basophilic

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 RER cont…
• Functions:
– Synthesis & segregation of proteins for export
– Initial (core) glycosylation of glycoproteins
– Assembly of multichain proteins
– Certain post transitional modifications of newly
formed polypeptides
– It makes the digestive enzymes that will be
contained in lysosomes.
– The rough ER can be considered the “cell’s
membrane factory.”

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 Smooth Endoplasmic Reticulum
• Irregular network of memb-bounded channels, lacks
ribosomes
• Usually appears as branching anastomosing tubules,
or vesicles.
• Less common than RER, predominates in cells
synthesizing steroids, triglycerides, & cholesterol.
• SER is abundant in liver cell & muscle cell
• SER cisternae are often more tubular and
more likely to appear as interconnected channels

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 Smooth ER cont…
• Functions
– Steroid hormone synthesis : Leydig cells, Zona
fasiculta (Suprarenal gland)
– Drug detoxification: Hepatocytes
– Muscle contraction & relaxation : Skeletal m.
(sarcoplasmic reticulum, release & recapture of
Ca++)
– Metabolism of lipid (phospholipid synthesis)
& cholesterol
– Glycogen synthesis, storage & breakdown in the
liver

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 Golgi Apparatus
• Consist of several disc-shaped cisternae (saccules)
arranged in stack.
• Cisternae are slightly curved with flat centres & dilated
rims.
• Material moves from the RER cisternae to the Golgi
apparatus in small, membrane-enclosed carriers called
transport vesicles.
• The transport vesicles merge with the Golgi-receiving
region, or cis face.
• At trans face, larger saccules or vacuoles accumulate,
condense, and generate other vesicles that carry
completed protein products to organelles.
.

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 Golgi Apparatus cont…
• Regions
– Cis (entry) face
• Forming (outer, convex) cisternae at side of the
stack facing the RER.
– Trans (exit) face
• Maturing (inner, concave) cisternae at side of the
stack facing vacuoles & secretory granules.
– Medial compartment
• Few cisternae between the cis & trans faces.
– Trans Golgi network (TGN)
• Lies apart from the last cisterna at the trans face
and is separated from the Golgi stack
• Corresponds to a tubular reticulum formerly
called GERL (Golgi-associated endoplasmic
reticulum from which lysosomes originate).
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 Golgi Apparatus cont…
Functions
– Processing of noncytosolic proteins synthesized in
RER.
– Membrane retrieval, recycling & redistribution
– Glycosylation, sulfation & phosphorylation
– Initiation of packing, concentration & storage of
secretory products
– Limited proteolysis of proteins

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 Lysosomes
• Lysosomes are sites of intracellular digestion and
turnover of cellular components.
• Lysosomes are membrane-limited vesicles that contain
about 40 different hydrolytic enzymes.
• The most common are acid hydrolyases such as
proteases, nucleases, phosphatase, phospholipases,
sulfatases, and β-glucuronidase.
• Phagocytic cells, such as some white blood cells
(macrophage & neutrophil), have an exceptional
number of lysosomes to degrade ingested bacteria and
viruses.

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 Lysosomes cont…
• Cytosolic components are protected from these
enzymes by the membrane surrounding lysosomes
and because the enzymes have optimal activity at an
acidic pH (~5.0).
• Any leaked lysosomal enzymes are practically inactive
at the pH of cytosol (~7.2) and harmless to the cell.
• Lysosomal hydrolases are synthesized and segregated
in the RER and then transferred to the Golgi
apparatus.
• Lysosomes also function in the removal of excess or
nonfunctional organelles and other cytoplasmic
structures in a process called autophagy
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 Lysosomes cont…
• Phagocytic vacuoles (phagosomes) fuse with primary
lysosomes to become secondary lysosomes
(heterolysosomes), in which ingested material is
degraded.
• Autophagosomes, are formed after nonfunctional or
surplus organelles become enclosed with membrane
and the resulting structure fuses with a lysosome.
• The products of lysosomal digestion are recycled to
the cytoplasm, but indigestible molecules remain in a
membrane-enclosed residual body.

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 Types of Lysosomes
1. Multivesicular bodies
• Formed by fusion of an early endosome containing
endocytic vesicles with a late endosome.
2. Phagolysosome
• Formed by fusion of a phagocytic vacuole with a late
endosome or lysosome.
3. Autophagolysosome
• Formed by fusion of an autophagic vacuole with a late
endosome or lysosome.
4. Residual bodies
• Lysosomes that have expended their capacity to degrade
material
• Contain undigested material (lipofuscin, hemosiderin).
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 FUNCTIONS OF LYSOSOMES
• Intracellular digestion
• Degeneration of glycogen & its removal
• Initiate mitosis
• Release of thyroid hormones
• Destruction of bone matrix (osteoclasts)

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 TAY-SACHS DISEASE
• In Tay-Sachs disease, an infant’s lysosomes lack a
specific enzyme that breaks down certain
glycolipids (Hexosaminidase-A).
• Such glycolipids are especially abundant in the
membranes of nerve cells.
• Accumulation of undigested glycolipids in the
lysosomes interferes with nerve cell function,
resulting in mental retardation, blindness, spastic
movements, and death of the child within a year
and a half of birth.

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 Mitochondria
• Mitochondria produce energy for cellular function.
• The number of mitochondria is related to the
cell’s energy needs.
• Cells with a high-energy metabolism (e.g., cardiac
muscle, cells of some kidney tubules) have abundant
mitochondria.
• Mitochondria are enclosed by two membranes:
– This membranes create two compartments: the innermost
matrix and a narrow intermembrane space.
• Both mitochondrial membranes contain a higher
density of protein molecules than other and have
reduced fluidity.
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 Mitochondria cont…
• The outer membrane is smooth, sieve-like, containing
many transmembrane proteins called porins
– This form channels through which small molecules
such as pyruvate and other metabolites readily pass
from the cytoplasm to the intermembrane space.
– Metabolites such as pyruvate and fatty acids enter
mitochondria via membrane porins and are converted
to acetyl CoA by matrix enzymes of the citric acid
cycle or Krebs cycle.
• Yielding some ATP and NaDH (nicotinamide adenine
dinucleotide), a major source of electrons for the
electrontransport chain.

67
 Mitochondria cont…
• The inner membrane is folded to form a series of long
infoldings called cristae, which project into the matrix.
– The innermost mitochondrial matrix is a gel containing
numerous enzymes
– Contain the ATP synthase complexes that generate most of
the cell’s ATP.
• The number of cristae in mitochondria also corresponds
to the energy needs of the cell

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 Mitochondria cont…
• Contain some maternally inherited genetic material
(DNA) and divide to form new mitochondria.
• Unlike most organelles mitochondria are partly
autonomous of nuclear genes and activities.
• The mitochondrial matrix contains a small circular
chromosome of DNA, ribosomes, mRNA, and tRNA.
• Protein synthesis occurs in mitochondria.
– However, because of the reduced amount of mitochondrial
DNA, only a small subset of mitochondrial proteins is
produced locally.

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 Peroxisomes
• Peroxisomes (“peroxide bodies”) are like the toxic
waste removal system of the manufacturing plant.
• Peroxisomes (“peroxide bodies”) are single membrane-
walled sacs that resemble small lysosomes.
• They contain a variety of enzymes, most importantly
oxidases and catalases.
• Free radicals are normal by-products of cellular
metabolism, but if allowed to accumulate they can
destroy the cell’s proteins, membranes, and DNA.

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 Peroxisomes cont…
• Oxidases use oxygen to neutralize free radicals,
converting these to hydrogen peroxide.
• Hydrogen peroxide is also reactive and dangerous, but it
is converted by catalase into water and oxygen.
• Peroxisomes form in two ways: budding of precursor
vesicles from the ER or growth and division of
preexisting peroxisomes.
• Peroxisomes are numerous in liver and kidney cells

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 Functions of Peroxisomes
• Regulates H2O2 within cells
• Gluconeogenesis (formation of glucose from
non carbohydrate precursors)
• Enzymes for lipid metabolism: β-oxidation of
long chain FAs
• Detoxification (e.g., ethanol)
• Formation of bile salts

73
 Cytoskeleton
• The cytoskeleton, literally “cell skeleton,” is an
elaborate network of rods running throughout the
cytosol.
• This network acts as a cell’s “bones,” “muscles,”
and “ligaments” by supporting cellular structures
and generating various cell movements.
The three types of rods in the cytoskeleton are:
• Microfilaments
• Intermediate filaments
• Microtubules, none of which is covered by a
membrane.
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 Microfilaments
• The thinnest elements of the cytoskeleton (7 nm),
are strands of the protein actin.
• They concentrate deep to the plasma membrane.
• They interact with myosin to generate contractile
forces within the cell.
• Additionally, myosin acts as a motor protein to
move some organelles within the cell.

75
 Intermediate filaments
• Intermediate filaments are tough, insoluble protein
fibers, with a diameter of (10 nm).
• They are the most stable and permanent of the
cytoskeletal elements.
• Have high tensile strength; act like strong guy-wires to
resist pulling forces that are placed on the cell.
• They also function to link adjacent cells together.

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 Intermediate filaments cont…

• Intermediate filament proteins with particular

biological, histological, or pathological importance
include the following:
– Keratins (Gr. keras, horn) or cytokeratins are a
diverse family of acidic and basic isoforms that
compose heterodimer subunits of intermediate
filaments in all epithelial cells
– Vimentin is the most common class III intermediate
filament protein and is found in most cells derived
from mesenchyme.

77
 Intermediate filaments cont…

• Important vimentin-like proteins include

desmin found in almost all muscle cells and glial
fbrillar acidic protein (GFAP) found especially in
astrocytes.
– Neurofilament proteins of three distinct sizes
make heterodimers that form the subunits of the
major intermediate filaments of neurons.
– Lamins are a family of seven isoforms present in
the cell nucleus, where they form a structural
framework called the nuclear lamina just inside
the nuclear envelope

78
 Microtubules
• Microtubules, the elements with the largest
diameter (25 nm), made of spherical protein
called tubulins.
• They are stiff but bendable.
• Microtubules determines the overall shape of
the cell, as well as the distribution of cellular
organelles.

79
80
 Centrioles
• It contains no membranes.
• The wall of each centriole consists of 27 short
microtubules, arranged in nine groups of three.
• Unlike most other microtubules, those in
centrioles are stable and do not disassemble.
• Functionally, centrioles act in forming cilia and
flagella.

81
 Cytoplasmic Inclusions
• Unlike organelles, cytoplasmic inclusions are
composed mainly of accumulated metabolites.
• It is nonmotile with little or no metabolic
activity.
• Inclusions are not considered organelles.
Important and commonly seen inclusions include:
Fat droplets, accumulations of lipid molecules
that are prominent in adipocytes (fat cells),
adrenal cortex cells, liver and other cells.

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 Cytoplasmic Inclusions cont…
Glycogen granules, aggregates of a
carbohydrate polymer in which glucose is
stored and visible in several cell types, mainly
liver cells.
Lipofuscin granules, small pigmented (golden-
brown) bodies present in many cells, but which
accumulate with age in stable non dividing cells
(e.g., neurons, cardiac muscle).

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 Cytoplasmic Inclusions cont…

Hemosiderin: is a dense brown aggregate

of denatured ferritin proteins with many atoms of
bound iron.
– It occurs in phagocytic cells, especially
macrophages of the liver and spleen, where it
results from phagocytosis of red blood cells

84
 Nucleus
• The nucleus, literally a “little nut,” is the control
center of the cell.
• Its genetic material, deoxyribonucleic acid (DNA)
directs the cell’s activities by providing the
instructions for protein synthesis.
Most cells have only one nucleus, but some has:
• Binucleated: parietal cells (stomach), some
hepatocytes, some cardiac muscle cells.
• Multinucleated: osteoclasts, skeletal muscle cells.
• No nuclei at all: erythrocytes, blood platelets.
85
 Nucleus cont…
• The nucleus, which averages 5 μm in diameter, is
larger than any of the cytoplasmic organelles.
• Usually spherical or oval in shape.
• The main parts of the nucleus are:
➢ Nuclear envelope
➢ Nucleolus, and
➢ Chromatin and chromosomes.

86
87
 Nuclear Envelope
• The nucleus is surrounded by a double layer
nuclear envelope.
• The nuclear envelope encloses a jellylike fluid
called nucleoplasm.
• The membranes of the nuclear envelope are
selectively permeable, but the nuclear pores
allow large molecules to pass in and out of the
nucleus as necessary.
• E.g., protein molecules imported from the
cytoplasm and RNA molecules exported from the
nucleus routinely travel through the pores. 88
 Nucleolus
• Well-defined, not memb-bounded nuclear
inclusion.
• Actively synthesize proteins (contains histones,
enzymes & RNA).
• Generally detectable only during interphase.
• The nucleolus is the site of synthesis of
ribosomal RNA and ribosome formation

89
➽ contains the following distinct regions:
1. Fibrillar centers
• Spherical areas of inactive rRNA surrounded by a dense fibrillar
region
2. Fibrillar regions
• Composed of fibrils (5nm in diameter) around and b/n the
fibrillar centers
• Contain transcriptionally active rRNA
• Represent early stages in the formation of rRNA precursors
3. Granular regions
• Are composed of 15nm particles representing maturing
ribosomal precursors

90
 Chromatin and Chromosomes
• The DNA molecule plus the proteins form chromatin.
• During cell division, the chromatin is further packed
into the most complex structure called chromosome
(“colored body”). There are 46 chromosomes in a typical
human cell.
• When a cell is dividing, its chromosomes are maximally
coiled.
• When cell division stops, chromosome uncoil to form
the extended chromatin.

91
 Types of Chromatin
Heterochromatin
➢ Intensively basophilic (electron-dense)
➢ Condensed chromatin (coiled portions of chromosomes)
➢ Transcriptionally inactive (gene transcription
suppressed)
Euchromatin (Interchromatin)
• Dispersed (diffuse) region of chromosomes
• Transcriptionally active (active DNA, control metabolic
activities)
• More prominent in metabolically active cells

92
 Cell cycle
• Sequence of events that is executed repetitively: repeated
divisions at regular intervals
• Dynamic & continuous process.
• Induced by phytohemagglutinin
• Arrested in metaphase stage by colchicine (chalones)
• Consists of two major periods
– Interphase: interval between cell divisions.
– Mitosis: periods of cell division (M phase).
 Cell cycle cont…
Interphase:
– Considerably longer than the M phase
– Cell doubles in size and DNA content
Phases
G1 (gap1) phase, S (synthesis) phase, and G2 (gap2)
phase
1.G1 Phase .
– The longest and the most variable phase of the
cell cycle, and it begins at the end of M phase.
– The cell gathers nutrients and synthesizes RNA
and proteins necessary for DNA synthesis and
chromosome replication

94
 G1 Phase cont…
• The cell’s progress through this phase is monitored by
two checkpoints:
– 1. The restriction point, which is sensitive to the size of
the cell, the state of the cell’s physiologic processes, and its
interactions with extracellular matrix; and
– 2. The G1 DNA-damage checkpoint, which monitors the
integrity of newly replicated DNA.

95
96
 Restriction point
• The restriction point (or “point of no return”) is the
most important checkpoint in the cell cycle.
• At this checkpoint, the cell self-evaluates its own
replicative potential before deciding to either enter the
S phase and the next round of cell division or to retire
and leave the cell cycle.
• A cell that leaves the cycle in the G1 phase usually
begins terminal differentiation by entering the GO
phase (“O” stands for “outside” the cycle).

97
 Cell cycle cont…

2. S Phase
✓ DNA replication & protein synthesis = duplication
of chromosomes
✓ Centrioles self-duplicate
✓ Lasts 8-12 hours in most cells.
3. G2 Phase
– Cell prepares to divide
– Centrioles grow to maturity
– Energy required for the completion of mitosis is
restored
– RNA & proteins necessary for mitosis are
synthesized
– Lasts 2-4 hours.
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 Mitosis
• Cell division is a crucial process that increases the
number of cells, permits renewal of cell populations,
and allows wound repair.
• A parent cell divides and each of the two daughter cells
receives a chromosomal set identical to that of the
parent cell.
• The process of cell division includes division of both
the nucleus (karyokinesis) and the cytoplasm
(cytokinesis).
• The process of cytokinesis results in distribution of
nonnuclear organelles into two daughter cells

99
 Mitosis cont…
• It is the only cell cycle phase that can be
routinely observed with the light microscope.
• The events of mitosis can be subdivided into
four phases
– Prophase
– Metaphase
– Anaphase
– Telophase

100
 Prophase
• Begins as the replicated chromosomes condense and
become visible.
• Each chromosomes to consist of two sister chromatids.
• The sister chromatids are held together by the ring of
proteins called cohesins and the centromere.
Late prophase (prometaphase)
• The nuclear envelope begins to disintegrate into small
transport vesicles and resembles the SER.
• The nucleolus completely disappears.

101
 Metaphase
• Begins as the mitotic spindle, becomes organized
around the microtubule-organization centers
(MTOCs) located at opposite poles of the cell
• Kinetochore microtubules and their associated motor
proteins direct the movement of the chromosomes to a
plane in the middle of the cell, the equatorial or
metaphase plate.

102
 Anaphase
• Begins at the initial separation of sister chromatids.
• This separation occurs when the cohesins that have
been holding the chromatids together break down.
• The chromatids then begin to separate and are pulled
to opposite poles of the cell by the molecular motors
(dyneins) sliding along the kinetochore
microtubules toward the MTOC

103
 Telophase
• It is marked by the reconstitution of a nuclear
envelope around the chromosomes at each pole.
• The chromosomes uncoil and become indistinct.
• The nucleoli reappear, and the cytoplasm divides
(cytokinesis) to form two daughter cells.
• Cytokinesis begins with the furrowing of the plasma
membrane midway between the poles of the mitotic
spindle.

104
Figure: mitosis
• The chromosomes of maternal and
paternal origin are depicted in red
and blue, respectively.
• The mitotic division produces
daughter cells that are
genetically identical to the
parental cell (2n).

105
 Meiosis
• Meiosis is a specialized process involving two unique
and closely associated cell divisions.
• Occurs only in the cells that will form sperm and egg
cells.
• Two key features characterize meiosis.
– Early in the process the homologous chromosomes of
each pair (one from the mother, one from the father)
come together in an activity termed synapsis.
• During synapsis double-stranded breaks and repairs
occur in the DNA.
• Some of which result in reciprocal DNA exchanges
called crossovers between the aligned maternal and
paternal chromosomes. 106
A. Homologous chromosomes approach each other. B. Homologous chromosomes pair, and each member of the pair
consists of two chromatids. C. Intimately paired homologous chromosomes interchange chromatid fragments
(crossover). Note the chiasma. D. Double-structured chromosomes pull apart. E. Anaphase of the first meiotic
division. F,G. During the second meiotic division, the double-structured chromosomes split at the centromere. At
completion of division, chromosomes in each of the four daughter cells are different from each other.
 Meiosis cont…
• Crossing over produces new combinations of genes in
the chromosomes in the germ cells
– The cells produced are haploid, having just one
chromosome from each pair present in the body’s somatic
cells.
• The union of haploid eggs and sperm at fertilization
forms a new diploid cell (the zygote) that can develop
into a new individual

108
 Cont…
• Mitosis is a cell division that produces two diploid
cells.
• Meiosis involves two cell divisions and produces
four haploid cells
• During meiotic crossing over, new combinations of
genes are produced and every haploid cell is
genetically unique.
• Lacking synapsis and the opportunity for DNA
recombination, mitosis yields two cells that are the
same genetically.

109
 Cell renewal
• Somatic cells in the adult organism may be
classified according to their mitotic activity
• Cell populations may be classified as
– Static
– Stable
– Renewing

110
 Static cell populations
• Consist of cells that no longer divide (postmitotic
cells), such as cells of the central nervous system and
skeletal or cardiac muscle cells.
• Under certain circumstances some of these cells (i.e.,
cardiac myocytes) may enter mitotic division.

111
 Stable cell populations
• Consist of cells that divide episodically and slowly to
maintain normal tissue or organ structure.
• These cells may be stimulated by injury to become
more mitotically active.
• Periosteal and perichondrial cells, smooth muscle
cells, endothelial cells of blood vessels, and
fibroblasts of the connective tissue may be included
in this category

112
 Renewing cell populations
• May be slowly or rapidly renewing but display
regular mitotic activity.
• Division of such cells usually results in two daughter
cells that differentiate both morphologically and
functionally or two cells that remain as stem cells.
• Daughter cells may divide one or more times before
their mature state is reached.
• The differentiated cell may ultimately be lost from
the body.

113
 Renewing cell populations
• Slowly renewing populations include smooth
muscle cells of most hollow organs, fibroblasts of
the uterine wall, and epithelial cells of the lens of
the eye.
• Slowly renewing populations may actually slowly
increase in size during life, as do the smooth muscle
cells of the gastrointestinal tract and the epithelial
cells of the lens.
• Rapidly renewing populations include blood cells,
epithelial cells and dermal fibroblasts of the skin,
and the epithelial cells and subepithelial fibroblasts
of the mucosal lining of the alimentary tract.
114
 Cell Death
• In humans, the rates of cell proliferation and cell death
determine the net cell production.
• An abnormality in any of these rates can cause
– Disorders of cell accumulation (e.g., hyperplasia, cancer,
autoimmune diseases) or
– Disorders of cell loss (atrophy, degenerative diseases,
ischemic injury).
• Therefore, the balance (homeostasis) between cell
production and cell death must be carefully
maintained

115
 Cell death cont….
• Cell death may occur as a result of acute cell
injury or an internally encoded suicide program.
• Cell death may result from accidental cell injury or
mechanisms that cause cells to self-destruct.
• The major two different mechanisms of cell death
are:
– Necrosis and
– Apoptosis.

116
 Necrosis
• Necrosis, or accidental cell death, is a pathologic
process.
• It occurs when cells are exposed to an unfavorable
physical or chemical environment (e.g., hypothermia,
hypoxia, radiation, low pH, cell trauma) that causes
acute cellular injury and damage to the plasma
membrane.
• Under physiologic conditions, damage to the plasma
membrane may also be initiated by viruses, or
proteins called perforins.
• Rapid cell swelling and lysis are two characteristic
features of this process
117
 Apoptosis
• Apoptosis referred to as programmed cell death.
• It is applied more broadly to any kind of cell death
mediated by an intracellular death program,
irrespective of the trigger mechanism.
• Apoptosis represents a physiologic process.
• During apoptosis, cells that are no longer needed are
eliminated from the organism.
• Apoptosis is characterized by controlled autodigestion.
– The cell “dies with dignity” without spilling its contents and
damaging its neighbors.

118
Figure: Schematic diagram showing the relationship between cell death and
cell division.

119
 Apoptosis cont…
• Cells undergoing apoptosis show the following
characteristic morphologic and biochemical features

1. DNA fragmentation occurs in the nucleus and is an

irreversible event that commits the cell to die.
• DNA fragmentation is a result of Ca2+ dependent and
Mg2+ dependent activation of nuclear endonucleases.
• These enzymes selectively cleave DNA, generating
small oligonucleosomal fragments.

120
 Apoptosis cont…
2. Decrease in cell volume is achieved by shrinking of
the cytoplasm.
• The cytoskeletal elements become reorganized in
bundles parallel to the cell surface.
• Ribosomes become clumped within the cytoplasm, the
RER forms a series of concentric whorls, and most of
the endocytotic vesicles fuse with the plasma
membrane.

121
 Apoptosis cont…
3. Loss of mitochondrial function is caused by changes
in the permeability of the mitochondrial membrane
channels.
• The integrity of the mitochondrion is breached, the
mitochondrial transmembrane potential drops, and
the electrontransport chain is disrupted.
• Proteins from the mitochondrial intermembrane space,
such as cytochrome c, are released into the cytoplasm
to activate a cascade of proteolytic enzymes called
caspases that are responsible for dismantling the cell.

122
 Apoptosis cont…
• The regulated release of cytochrome c suggests that
mitochondria, are the decision makers for initiating
apoptosis.
• Thus, many researchers view mitochondria either as
the “headquarters for the leader of a crack suicide
squad” or as a “high-security prison for the leaders
of a military coup.

123
 Apoptosis cont…
4. Membrane blebbing results from cell membrane
alterations.
• One alteration is related to translocation of certain
molecules (e.g., phosphatidylserine).
• These changes cause the plasma membrane to change
its physical and chemical properties and lead to
blebbing without loss of membrane integrity

124
 Apoptosis cont…
5. Formation of apoptotic bodies, the final step of
apoptosis, results in cell breakage.
• These membrane-bounded vesicles originate from the
cytoplasmic bleb containing organelles and nuclear
material.
• They are rapidly removed without a trace by
phagocytotic cells.
• The removal of apoptotic bodies is so efficient that no
inflammatory response is elicited.
• Apoptosis occurs more than 20 times faster than
mitosis; therefore, it is challenging to find
apoptotic cells in a routine H&E preparation
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