17.4 Histology: Cells, Epithelium & Glands, Connective Tissue & Fat, Cartilage & Bone, Blood & Hematopoiesis, Muscle, Nerve, Vessels, Lymphoid Organs & Organ Histology

Why this area matters

The TOS histology list covers:

• the cell and cell division;
• epithelium;
• glands and secretion;
• blood and blood cell formation;
• connective, adipose and nervous tissue;
• muscles and bone;
• the organs of the body;
• the immune system;
• the nervous system (autonomic, central, peripheral, somatosensory and motor pathways, limbic system).

Histology underlies pathology: you must know normal tissue to recognize metaplasia, neoplasia and inflammation.

The cell and cell division (summary)

• Organelles and their functions are reviewed in general physiology: nucleus, rough and smooth ER, Golgi, lysosomes, peroxisomes, mitochondria, cytoskeleton.
• Mitosis has prophase, prometaphase, metaphase (chromosomes align; colchicine and vinca alkaloids block the spindle), anaphase and telophase, followed by cytokinesis.
• Meiosis has two divisions with crossing-over in prophase I and produces haploid gametes. Nondisjunction causes aneuploidy.
• Cells with high turnover (labile cells) are most sensitive to chemotherapy and radiation.

Epithelial Classifications & Functional Microarchitecture

Epithelial tissue lines external body surfaces, lines internal closed cavities and body tubes, and forms secretory glands. Epithelia exhibit cellular polarity (apical, lateral, and basal domains), rest upon an underlying basement membrane, and are fundamentally avascular, receiving metabolic support via passive diffusion from adjacent vascularized loose connective tissue (lamina propria).

Morphological Classification of Epithelia

1. Simple Squamous Epithelium:

   • Composed of a single layer of attenuated, flattened polygonal cells with central, bulging disc-like nuclei.
   • Primary functions: rapid passive diffusion of gases and solutes, fluid filtration, and transcellular transport.
   • Canonical anatomical sites: vascular and lymphatic lining (endothelium), serous cavity linings of the pleura, peritoneum, and pericardium (mesothelium), pulmonary alveoli (Type I pneumocytes), the parietal layer of Bowman's capsule in the renal corpuscle, and the thin limbs of the loop of Henle.

2. Simple Cuboidal Epithelium:

   • Composed of a single layer of cells whose height and width are approximately equal, with spherical, centrally positioned nuclei.
   • Primary functions: active solute absorption, barrier maintenance, and cellular secretion.
   • Canonical anatomical sites: renal proximal convoluted tubules (possessing an apical brush border of microvilli) and distal convoluted tubules, thyroid follicular epithelium (varying from flat-cuboidal in inactivity to tall-columnar during TSH hyperstimulation), the surface lining of the ovary (germinal epithelium of Waldeyer), and the secretory ducts of small exocrine glands.

3. Simple Columnar Epithelium:

   • Composed of tall, rectangular cells whose apical-to-basal height substantially exceeds their width, with oval nuclei aligned in the basal third of the cytoplasm.
   • Non-ciliated variety: Lines the entire luminal gastrointestinal tract from the gastric cardia and stomach through the small and large intestines to the anorectal junction. In the small intestine, it features a prominent apical brush border of uniform microvilli (anchored into a terminal web of actin microfilaments) alongside mucin-secreting goblet cells to optimize nutrient absorption.
   • Ciliated variety: Lines the uterine (fallopian) tubes and small bronchioles. In the oviduct, coordinated ciliary beating sweeps the ovum toward the uterine cavity.

4. Stratified Squamous Epithelium:

   • Multilayered architecture designed specifically to resist severe mechanical abrasion, shear stress, and chemical trauma. The basal layer undergoes continuous mitotic division, while differentiating cells flatten as they ascend toward the free apical surface.
   • Non-keratinized stratified squamous: Superficial cells retain viable, flattened nuclei. Found on moist mucosal surfaces subject to mechanical friction: oral cavity, pharynx, esophagus, vocal folds, vagina, ectocervix, anal canal below the pectinate line, and the anterior corneal epithelium.
   • Keratinized stratified squamous: Superficial cell layers lose their nuclei and cytoplasmic organelles, transforming into compact, enucleated scales filled with cytokeratin filaments and cross-linked envelope proteins (stratum corneum). Forms the protective epidermis of the skin, preventing transcutaneous water loss and microbial invasion.

5. Pseudostratified Columnar Epithelium:

   • Appears multi-layered because cell nuclei are positioned at differing levels, but all individual cells remain in physical contact with the basement membrane. Not all cells reach the apical luminal surface.
   • Respiratory epithelium: Pseudostratified ciliated columnar epithelium intercalated with mucin-secreting goblet cells and basal stem cells. Lines the nasal cavity, paranasal sinuses, nasopharynx, larynx (except true vocal folds), trachea, and major bronchial tree.
   • Stereociliated variety: Found in the male reproductive tract (epididymis and ductus deferens); possesses extremely long, non-motile, actin-rich stereocilia functioning in fluid reabsorption and sperm maturation.

6. Transitional Epithelium (Urothelium):

   • Specialized stratified epithelium restricted entirely to the urinary tract: renal calyces, renal pelvis, ureters, urinary bladder, and proximal urethra.
   • Exhibits profound morphological plasticity: in the empty, contracted state, it appears 5 to 7 layers thick with rounded, dome-shaped superficial cells (umbrella cells); upon luminal distention, it stretches to 2 to 3 flattened layers without loss of structural continuity.
   • Apical membranes of umbrella cells possess rigid, thickened plaques composed of crystalline uroplakin proteins arranged in asymmetric unit membrane complexes that fold inward into cytoplasmic discoidal vesicles during bladder contraction and unfold to expand surface area during vesical filling, forming an impermeable osmotic barrier against hypertonic urine.

Epithelial Tissues: Morphological Classification & Anatomical Sites

Glands and secretion

• Exocrine glands secrete through ducts. They are classified by duct branching (simple or compound), shape (tubular, acinar or alveolar) and mode of secretion:
  • Merocrine (eccrine): exocytosis without loss of cytoplasm, as in salivary, pancreatic and eccrine sweat glands.
  • Apocrine: the apical cytoplasm is shed, as in apocrine sweat glands and lipid secretion in the mammary gland.
  • Holocrine: the whole cell disintegrates, as in sebaceous glands.
• Serous acini (parotid) secrete watery protein-rich fluid; mucous acini (sublingual) secrete mucin. Mixed glands (submandibular) have serous demilunes.
• Endocrine glands secrete into the blood and have a rich fenestrated capillary network: thyroid follicles, adrenal cortex zones, islets of Langerhans.

Connective, adipose and nervous tissue

• Connective tissue proper:
  • loose (areolar) connective tissue lies under epithelia;
  • dense irregular connective tissue forms the dermis and organ capsules;
  • dense regular connective tissue forms tendons and ligaments.
  • Fibroblasts make collagen, elastin and ground substance; mast cells, macrophages and plasma cells are resident cells. Collagen types are covered in Biochemistry.
• Adipose tissue:
  • White fat has unilocular cells with a peripheral nucleus ("signet ring") and stores energy.
  • Brown fat has multilocular cells packed with mitochondria containing thermogenin (UCP-1), which produces heat. It is prominent in newborns between the scapulae and around the kidneys.
• Nervous tissue: neurons (cell body with Nissl substance, which is rough ER, plus dendrites and an axon) and glia (see below).

Cartilage & Bone Histology

Cartilage Microarchitecture

Cartilage is an avascular specialized connective tissue nourished via solute diffusion through a gel-like proteoglycan-rich matrix. The matrix is maintained by chondrocytes residing within lacunae.

1. Hyaline Cartilage: Contains fine Type II collagen fibrils and aggrecan-chondroitin sulfate complexes. Possesses a vascularized perichondrium (except over articular cartilage surfaces and epiphyseal plates). Locations: articular joint surfaces, costal cartilages, thyroid and cricoid cartilages, tracheal and bronchial rings, and the embryonic skeletal template.
2. Elastic Cartilage: Contains Type II collagen plus dense anastomosing networks of elastic fibers (visualized with orcein or Verhoeff-van Gieson stain). Highly flexible, possesses a perichondrium. Locations: auricle (pinna) of the external ear, external acoustic meatus, auditory (Eustachian) tube, epiglottis, and the cuneiform and corniculate laryngeal cartilages.
3. Fibrocartilage: Characterized by dense bundles of Type I collagen running parallel to rows of chondrocytes in lacunae; intermediate between dense regular connective tissue and hyaline cartilage. Lacks a perichondrium. Resists extreme tensile and compressive forces. Locations: intervertebral discs (annulus fibrosus), pubic symphysis, temporomandibular joint articular disc, and knee menisci.

Bone Cells and Haversian Architecture

Bone is a dynamic, vascularized mineralized connective tissue composed of an organic osteoid matrix (90% Type I collagen, osteocalcin, osteopontin) impregnated with inorganic hydroxyapatite crystals ($Ca_{10}(PO_4)_6(OH)_2$).

• Osteoblasts: Derived from multipotent mesenchymal stem cells under the control of Runx2; cuboidal cells lining active bone surfaces; synthesize unmineralized osteoid; express alkaline phosphatase (ALP) (clinical serum marker of bone formation); express RANKL and secrete osteoprotegerin (OPG).
• Osteocytes: Terminally differentiated osteoblasts entrapped within calcified lacunae; communicate through extensive dendritic cytoplasmic filopodia traversing microscopic canaliculi; interconnected by gap junctions; act as mechanical strain sensors; secrete sclerostin to negatively regulate osteoblast activity.
• Osteoclasts: Large, multinucleated giant cells derived from the monocyte/macrophage hematopoietic lineage ($CD14^+$ precursors). Differentiation is driven when osteoblastic RANKL binds RANK on osteoclast precursors (a process competitively inhibited by OPG, which acts as a soluble decoy receptor). Osteoclasts resorb bone within shallow depressions called Howship lacunae:
  • The ruffled border seals against the bone matrix via $\alpha_v\beta_3$ integrins.
  • Carbonic anhydrase II generates carbonic acid, and vacuolar $H^+$-ATPase pumps protons into the subosteoclastic sealing zone, dissolving hydroxyapatite.
  • Lysosomal cathepsin K is exocytosed to cleave the organic Type I collagen matrix.

Compact Bone Organization

Cortical bone is organized into cylindrical structural units termed osteons (Haversian systems):

• A central Haversian canal transmits neurovascular structures longitudinally.
• Concentric lamellae of mineralized matrix encircle the Haversian canal.
• Transverse or oblique Volkmann canals (perforating canals) pierce the bone perpendicularly to link adjacent Haversian canals with the periosteum and endosteum.

Endochondral vs. Intramembranous Ossification

• Endochondral Ossification: Mesenchymal cells condense into a miniature hyaline cartilage model, which is subsequently invaded by osteogenic vascular buds; primary ossification centers form in the diaphysis, followed by secondary ossification centers in the epiphyses; separated by the epiphyseal growth plate (zones of reserve, proliferation, hypertrophy, calcification, and ossification). Forms the appendicular skeleton, vertebral column, and skull base (long bones and axial bones).
• Intramembranous Ossification: Mesenchymal stem cells differentiate directly into osteoblasts within vascularized embryonic mesenchyme without a prior cartilaginous scaffold; osteoid is deposited directly and mineralized into woven bone, subsequently remodeled into lamellar bone. Forms the flat bones of the calvarium (frontal, parietal, occipital), facial bones (maxilla, mandible), and the clavicle.

---

Vascular Microarchitecture & Capillary Dynamics

Blood vessel walls exhibit a classic three-layered concentric microarchitecture:

1. Tunica Intima: Comprises the luminal vascular endothelium (simple squamous cells resting on a basal lamina) and delicate subendothelial loose connective tissue. Endothelial cells synthesize prostacyclin ($PGI_2$), nitric oxide (NO), endothelin-1, and store von Willebrand factor (vWF) and P-selectin within specialized cytoplasmic Weibel-Palade bodies. An internal elastic lamina (IEL) forms the boundary between the intima and media, prominent in muscular arteries.
2. Tunica Media: Composed of circularly oriented vascular smooth muscle cells interspersed with elastic fibers, Type III collagen, and proteoglycans. In elastic conducting arteries (aorta, pulmonary trunk, carotid arteries), the media is dominated by 40 to 70 concentric, fenestrated elastic lamellae that recoil during diastole to maintain downstream perfusion (Windkessel effect). In muscular distributing arteries, the media consists of up to 40 layers of smooth muscle bounded externally by an external elastic lamina (EEL). In arterioles (1 to 3 smooth muscle layers), the media governs total peripheral vascular resistance (SVR) and systemic blood pressure.
3. Tunica Adventitia: External supporting fibroelastic sheath composed of longitudinally arranged Type I collagen, fibroblasts, autonomic nerve terminals (nervi vascularis), and microvascular channels (vasa vasorum, which nourish the outer half of thick arterial walls; occlusion of aortic vasa vasorum in tertiary syphilitic endarteritis obliterans causes thoracic aortic aneurysms).

Capillary Permeability Classifications

• Continuous Capillaries: Endothelial cells linked by tight junctions over an uninterrupted, continuous basal lamina; transcytosis occurs via pinocytotic vesicles; surrounded by contractile pericytes. Locations: brain (blood-brain barrier with astrocytic end-feet), skeletal and cardiac muscle, lungs, skin, and connective tissues.
• Fenestrated Capillaries: Endothelial cells possess transcellular cylindrical pores ($60\text{--}80\text{ nm}$) spanned by thin protein diaphragms; continuous basal lamina. Permits rapid, high-volume fluid and solute filtration. Locations: renal glomeruli (pores lack diaphragms), intestinal villi, endocrine glands, and choroid plexus.
• Sinusoidal (Discontinuous) Capillaries: Large-caliber, tortuous vascular channels with wide intercellular gaps, fenestrations lacking diaphragms, and an incomplete or entirely absent basal lamina. Permits unimpeded passage of plasma proteins and whole cellular elements. Locations: liver (flanked by Kupffer cells and hepatic stellate cells within the Space of Disse), spleen (sinusoids of the red pulp where erythrocytes undergo splenic filtration), and bone marrow.

Blood and blood cell formation

• Peripheral blood cells:
  • Red cells are biconcave and anucleate.
  • Neutrophils have 3 to 5 nuclear lobes.
  • Eosinophils have bilobed nuclei and red granules containing major basic protein.
  • Basophils have dark granules containing histamine.
  • Lymphocytes are small, round cells with a thin rim of cytoplasm.
  • Monocytes are large, with kidney-shaped nuclei.
  • Platelets are cytoplasmic fragments of megakaryocytes.
• Sites of hematopoiesis:
  • yolk sac (weeks 3 to 8);
  • liver (the main fetal site from about 6 weeks to birth) and spleen;
  • bone marrow (from about the fifth month onward);
  • in adults, the axial skeleton (vertebrae, sternum, ribs, pelvis, skull) and the proximal femur and humerus.
  • Extramedullary hematopoiesis returns to the liver and spleen in thalassemia and myelofibrosis.
• Lineages: a multipotent stem cell gives rise to myeloid progenitors (red cells, granulocytes, monocytes, platelets) and lymphoid progenitors (B, T and NK cells). Red-cell maturation runs from proerythroblast to normoblast (the nucleus is extruded), reticulocyte and erythrocyte.
• Marrow cellularity falls with age, roughly 100 minus age percent. Aplastic anemia shows a fatty marrow.

Muscle tissue (histology)

Vessels and capillaries

The arteries, veins and capillary types (continuous, fenestrated, sinusoidal) are included above. Remember that veins have a thin media, valves and a thick adventitia. Lymphatic capillaries are blind-ended, with overlapping endothelial cells and anchoring filaments.

The immune (lymphoid) system

• Primary lymphoid organs: bone marrow (B-cell development) and the thymus. The thymus has a cortex with immature T cells undergoing positive selection, and a medulla with Hassall corpuscles where negative selection occurs. It involutes after puberty.
• Lymph node: afferent lymphatics enter the subcapsular sinus. The cortex contains B-cell follicles with germinal centers, the paracortex contains T cells and high endothelial venules (where lymphocytes enter), and the medulla contains medullary cords (plasma cells) and sinuses. Efferent lymphatics leave at the hilum. Paracortical hyperplasia is typical of viral infections.
• Spleen:
  • White pulp: periarteriolar lymphoid sheaths (T cells) and follicles (B cells).
  • Red pulp: sinusoids and cords that remove old red cells and inclusions.
  • Asplenia raises the risk of infection with encapsulated bacteria (pneumococcus, meningococcus, Haemophilus influenzae type b). Howell-Jolly bodies appear in the blood.
• MALT: Peyer patches in the ileum, the tonsils and bronchial lymphoid tissue. M cells in Peyer patches sample gut antigens.

Histology of key organs

• Respiratory: the trachea has C-shaped hyaline cartilage and respiratory epithelium. Bronchioles lack cartilage and glands and have club (Clara) cells. Alveoli are lined by type I pneumocytes (gas exchange) and type II pneumocytes (surfactant and repair), with alveolar macrophages.
• GI tract: the wall has four layers: mucosa, submucosa (with Meissner plexus), muscularis externa (with Auerbach plexus) and serosa or adventitia.
  • The stomach has parietal cells (HCl, intrinsic factor) and chief cells (pepsinogen).
  • The duodenum has Brunner glands; the jejunum has prominent plicae; the ileum has Peyer patches.
  • The colon has crypts rich in goblet cells and no villi.
• Liver: the classic lobule centers on the central vein. The portal triad (hepatic artery, portal vein, bile duct) lies at the corners. Zone 1 (periportal) gets the most oxygen; zone 3 (centrilobular) is most sensitive to ischemia and to acetaminophen toxicity.
• Kidney:
  • the glomerulus has fenestrated endothelium, the glomerular basement membrane and podocytes;
  • proximal tubule cells have a brush border;
  • the juxtaglomerular apparatus (macula densa plus granular cells) controls renin release.

Nervous system histology

• Peripheral nerves are wrapped by endoneurium (around each fiber), perineurium (around each fascicle, part of the blood-nerve barrier) and epineurium (around the whole nerve).
• Ganglia: sensory (dorsal root) ganglia have pseudounipolar neurons with satellite cells; autonomic ganglia have multipolar neurons.
• Pathways:
  • the somatosensory pathways are the dorsal column and spinothalamic tracts;
  • the motor pathway is the corticospinal tract;
  • the limbic system (hippocampus, amygdala, cingulate gyrus, mammillary bodies) handles memory and emotion. These are covered in the physiology chapters.