Master Histology & Cell Biology
for USMLE Step 1

Core Concepts

Histology is the microscopic study of tissues, while Cell Biology focuses on cellular structure, function, and behavior. For USMLE Step 1, understand both normal morphology and underlying cellular mechanisms, as pathology often stems from disruptions at these levels.
I. Cell Organelles & Function:

• Nucleus: Contains genetic material (DNA), site of replication, transcription, RNA processing. Key components: nucleolus (rRNA synthesis, ribosome assembly), nuclear envelope (double membrane, nuclear pores).
• Mitochondria: Powerhouse of the cell; site of aerobic respiration (Krebs cycle, oxidative phosphorylation), ATP synthesis. Possesses its own circular DNA and ribosomes. Involved in apoptosis initiation.
• Endoplasmic Reticulum (ER):
  • Rough ER (RER): Studded with ribosomes, involved in synthesis of secreted, membrane-bound, and lysosomal proteins. Site of protein folding and modification (glycosylation).
  • Smooth ER (SER): Lacks ribosomes, involved in lipid synthesis, steroid hormone production, detoxification (cytochrome P450), and calcium storage (sarcoplasmic reticulum in muscle).
• Golgi Apparatus: Modifies, sorts, and packages proteins and lipids from the ER for secretion or delivery to other organelles (e.g., lysosomes). Cis-face receives, trans-face ships.
• Lysosomes: Contain hydrolytic enzymes (acid hydrolases) for intracellular digestion of waste materials and cellular debris, pathogens, or old organelles (autophagy). Maintained by an acidic pH (proton pump).
• Peroxisomes: Contain oxidative enzymes (catalase, oxidases), involved in fatty acid oxidation, detoxification (alcohol), and plasmalogen synthesis. Generate and detoxify hydrogen peroxide.
• Ribosomes: Synthesize proteins (translation). Free ribosomes make cytoplasmic proteins; RER-bound ribosomes make secreted/membrane/lysosomal proteins.
• Cytoskeleton: Provides structural support, cell shape, motility, intracellular transport.
  • Microtubules: Tubulin polymers; form cilia, flagella, mitotic spindles; transport via dynein/kinesin.
  • Microfilaments (Actin): Actin polymers; muscle contraction, cell motility, microvilli, cell division (cytokinesis).
  • Intermediate Filaments: Diverse protein family (e.g., keratin, desmin, vimentin, GFAP, lamins); structural support, cell-cell/cell-matrix junctions. Tissue-specific.

• Tight Junctions (Zonula Occludens): Occludins, claudins. Prevent paracellular movement of substances; form a selective barrier (e.g., blood-brain barrier).
• Adherens Junctions (Zonula Adherens): Cadherins, catenins, actin filaments. Belt-like junctions, provide mechanical strength, link adjacent cells.
• Desmosomes (Macula Adherens): Cadherins (desmoglein, desmocollin), intermediate filaments. Spot-like junctions, strong adhesion between cells, resist shearing forces.
• Hemidesmosomes: Integrins, intermediate filaments. Anchor epithelial cells to basement membrane.
• Gap Junctions: Connexons (connexins). Allow direct passage of small molecules/ions between adjacent cells; electrical and metabolic coupling.

• Epithelial Tissue: Covers surfaces, lines cavities, forms glands. Closely packed cells, avascular, basement membrane. Classified by layers (simple, stratified, pseudostratified) and cell shape (squamous, cuboidal, columnar). Specializations: cilia, microvilli.
• Connective Tissue: Supports, protects, binds other tissues. Cells (fibroblasts, mast cells, macrophages, adipocytes) widely dispersed in abundant extracellular matrix (ECM). ECM components: collagen (most abundant, Types I-IV), elastin, reticular fibers, ground substance (GAGs, proteoglycans, glycoproteins).
• Muscle Tissue:
  • Skeletal: Striated, voluntary, multinucleated, peripheral nuclei. Sarcomere (actin/myosin) is functional unit.
  • Cardiac: Striated, involuntary, branched, 1-2 central nuclei, intercalated discs (gap junctions, desmosomes, adherens junctions).
  • Smooth: Non-striated, involuntary, spindle-shaped, single central nucleus. Found in walls of hollow organs.
• Nervous Tissue: Neurons (conduct electrical impulses) and Glial cells (support, protect, nourish neurons). Myelin sheath (Schwann cells in PNS, oligodendrocytes in CNS) increases conduction speed.

• Cell Cycle: G1 (growth), S (DNA synthesis), G2 (growth, preparation for mitosis), M (mitosis/meiosis). Checkpoints regulate progression.
• Apoptosis: Programmed cell death; regulated, clean removal of cells. Characterized by cell shrinkage, chromatin condensation, DNA fragmentation, formation of apoptotic bodies (phagocytosed). No inflammation. Caspases are key enzymes.
• Necrosis: Unregulated cell death due to injury; cell swelling, rupture, inflammation.

Clinical Presentation

• Lysosomal Storage Diseases (e.g., Tay-Sachs, Gaucher, Pompe): Accumulation of undigested substrates within lysosomes due to enzyme deficiencies. Presents with organomegaly, neurodegeneration, skeletal abnormalities.
• Mitochondrial Diseases: Dysfunction of ATP production. Variable presentations, often multi-systemic (muscle weakness, neurological deficits, lactic acidosis, vision/hearing loss).
• ER Stress / Unfolded Protein Response: Accumulation of misfolded proteins in ER. Contributes to neurodegenerative diseases (e.g., Alzheimer's, Parkinson's) and diabetes.
• Ciliary Dysfunction (Primary Ciliary Dyskinesia/Kartagener Syndrome): Defect in dynein arms of cilia/flagella. Presents with recurrent respiratory infections, situs inversus, infertility (immotile sperm).
• Collagen/Elastin Defects (e.g., Ehlers-Danlos, Marfan Syndrome): Abnormal ECM leading to hyperelastic skin, hypermobile joints, easy bruising, vascular fragility (Marfan).
• Junctional Defects (e.g., Pemphigus Vulgaris, Bullous Pemphigoid): Autoimmune diseases targeting desmosomes (pemphigus) or hemidesmosomes (pemphigoid), causing blistering of skin/mucosa.
• Abnormal Cell Proliferation/Apoptosis: Underlies cancer (uncontrolled growth, inhibited apoptosis) and autoimmune diseases (insufficient apoptosis of self-reactive lymphocytes).
• Metaplasia/Dysplasia: Reversible (metaplasia: one mature cell type replaced by another, e.g., Barrett's esophagus) or potentially reversible (dysplasia: disordered cell growth, architectural disarray) changes in epithelia, often pre-cancerous.

Diagnosis (Gold Standard)

The gold standard for diagnosing many cellular and tissue pathologies relies on microscopic examination of tissue biopsies. This involves:
I. Light Microscopy (LM): Routine examination of hematoxylin and eosin (H&E) stained sections. H&E provides general morphology (nuclei blue/purple, cytoplasm pink). Specific features like nuclear pleomorphism, mitotic figures, and architectural distortion are crucial for cancer diagnosis. Special stains (e.g., PAS for glycogen/mucus, Masson's Trichrome for collagen, Congo Red for amyloid) highlight specific components.
II. Electron Microscopy (EM): Provides higher resolution imaging of subcellular structures (organelles, viruses). Essential for diagnosing specific mitochondrial disorders, ciliary defects (e.g., dynein arm absence), or renal diseases (e.g., podocyte effacement).
III. Immunohistochemistry (IHC): Uses antibodies to detect specific proteins (antigens) within cells or tissues, allowing identification of cell lineage (e.g., cytokeratins for epithelial cells, vimentin for mesenchymal cells, CD markers for lymphocytes), presence of specific receptors, or infectious agents. Crucial for tumor classification and prognosis.
IV. Molecular/Genetic Testing: Identifies gene mutations, deletions, or rearrangements that cause many inherited cellular diseases (e.g., lysosomal storage disorders, muscular dystrophies).

Management (First Line)

Management strategies stemming from histological and cell biology diagnoses are highly diverse and disease-specific. For many genetic/inherited conditions, first-line management often includes supportive care, addressing symptoms and preventing complications. For enzyme deficiencies (e.g., some lysosomal storage diseases), enzyme replacement therapy (ERT) may be available. For neoplastic processes identified by histology, surgical resection, chemotherapy, and/or radiation therapy are standard. Advances in cell biology also enable targeted therapies that interrupt specific cellular signaling pathways or restore normal cellular function. Genetic counseling is crucial for inherited disorders.

Exam Red Flags