Hemopoiesis (Hematopoiesis)

Definition

"All formed elements of blood — red cells, granulocytes, monocytes, platelets, and lymphocytes — have a common origin from HSCs, pluripotent cells that sit at the apex of a hierarchy of bone marrow progenitors." — Robbins, Cotran & Kumar: Pathologic Basis of Disease

Sites of Hemopoiesis Through Life

Cell Hierarchy

Fig. 13.1 — Differentiation of blood cells (Robbins Pathology)

• Lymphoid lineage → B cells, T cells, NK cells
• Myeloid lineage → Neutrophils, Monocytes, Eosinophils, Basophils, Megakaryocytes (→Platelets), Erythrocytes

Regulation of Hemopoiesis

Two Essential Properties of HSCs

1. Pluripotency — ability to generate all mature blood cell types
2. Self-renewal — at least one daughter cell must remain a stem cell to prevent HSC depletion

Growth Factors Regulating Erythropoiesis

Fig. 45-1 — Sites of action of hematopoietic growth factors (Goodman & Gilman's Pharmacological Basis of Therapeutics)

Stage 1 — Early / Multilineage Factors (act on stem cells and early progenitors)

1. Stem Cell Factor (SCF) / c-Kit Ligand

• Acts as a mitogen for all hematopoietic progenitor cells, including the earliest erythroid progenitors (BFU-E)
• Produced by stromal cells of the bone marrow
• Works synergistically with EPO to expand the erythroid progenitor pool
• Binds the c-Kit receptor on stem cells

2. FLT3 Ligand (FL)

• Works alongside SCF at the stem cell level
• Promotes survival and expansion of multipotent progenitors before lineage commitment
• Acts on CFU-GEMM (mixed myeloid progenitors that include erythroid potential)

3. Interleukin-3 (IL-3)

• A broad-acting cytokine produced by T lymphocytes
• Stimulates proliferation of most progenitor cells, including early erythroid progenitors (BFU-E and CFU-GEMM)
• Synergizes with EPO at early stages; its effect diminishes at the CFU-E stage
• Does not directly drive terminal erythroid differentiation

4. GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor)

• Produced by T cells, endothelial cells, and fibroblasts
• Stimulates early multipotent progenitors including CFU-GEMM and early BFU-E
• Acts synergistically with EPO at early stages
• Less specific than EPO — also promotes granulocyte and monocyte lineages

Stage 2 — Late / Lineage-Specific Factor (acts on committed erythroid progenitors)

5. Erythropoietin (EPO) ⭐ — The Primary Regulator

"Erythropoietin is the most important regulator of the proliferation of committed erythroid progenitors (CFU-E) and their immediate progeny." — Goodman & Gilman's Pharmacological Basis of Therapeutics

• Prolyl hydroxylases hydroxylate HIF-1α (hypoxia-inducible factor)
• VHL (von Hippel-Lindau) protein recognizes hydroxylated HIF-1α → targets it for polyubiquitination and proteasomal degradation
• EPO gene expression is suppressed

• Prolyl hydroxylases are inactive (require O₂)
• HIF-1α accumulates and dimerizes with HIF-1β
• HIF complex translocates to nucleus → binds hypoxia-response elements → activates EPO gene transcription
• A second isoform, HIF-2α, is also a critical regulator of EPO expression and iron absorption genes

Clinical relevance: Mutations causing constitutive HIF-1α or HIF-2α accumulation (e.g., VHL loss-of-function) → chronically elevated EPO → polycythemia vera-like erythrocytosis.

Summary: Growth Factors by Stage

Negative Regulators of Erythropoiesis

• TGF-β (Transforming Growth Factor-β) — suppresses erythroid progenitor proliferation
• IFN-γ and TNF-α — suppress EPO secretion and progenitor proliferation (mechanism of anemia of chronic disease/inflammation)
• Hepcidin — produced by the liver in response to inflammation; blocks iron release from macrophages and enterocytes, reducing iron availability for erythropoiesis

Nutritional Cofactors (Required for Erythropoiesis)

• Iron — for hemoglobin synthesis
• Vitamin B12 and Folate — for DNA synthesis (deficiency → megaloblastic anemia)
• Vitamin B6 (Pyridoxine) — for heme synthesis

The Thymus and Its Role in the Body

What Is the Thymus?

(a) Child's thymus (left) — large and prominent; Adult's thymus (right) — involuted and replaced by adipose tissue. (b) Child's histology showing cortex (Co), medulla (M), septa (S), capsule (C). (c) Adult's involuted thymus embedded in fat (A). — Junqueira's Basic Histology

Development and Involution

Age-related thymic involution reduces the output of naïve T cells and may contribute to the decline of immune function in the elderly.

Gross and Microscopic Structure

Cortex (outer, darkly staining)

• Densely packed with thymocytes (immature T lymphocytes) — the most proliferative zone
• Contains thymic epithelial cells (TECs) that form a cytoreticulum (meshwork scaffold)
• Cortical TECs act as antigen-presenting cells (APCs), expressing both MHC class I and II molecules
• Cortical TECs secrete IL-7 — required early in T cell development
• Surrounded by squamous TECs that form the blood-thymus barrier, preventing unregulated antigen exposure during T cell education

Medulla (inner, lightly staining)

• Contains fewer, more mature lymphocytes
• Contains medullary TECs (MTECs) — express tissue-specific antigens from other organs → drive negative selection
• Contains the hallmark structure: Hassall's corpuscles (thymic corpuscles)

Hassall's Corpuscles

Thymic medulla: Hassall's corpuscles (HC) and epithelial cells (E) among lymphocytes — Junqueira's Basic Histology

Primary Role: T Cell Maturation and Education

Stage 1 — Entry and Early Proliferation

• Immature T cell progenitors (thymocytes) enter the thymus via blood vessels
• They begin maturation in the cortex, proliferating under the influence of IL-7 from cortical TECs
• Double-negative (CD4⁻CD8⁻) → Double-positive (CD4⁺CD8⁺) thymocytes

Stage 2 — Positive Selection (Cortex)

• Thymocytes whose T cell receptors (TCRs) can recognize self-MHC molecules survive
• Those that cannot recognize self-MHC → die by apoptosis (death by neglect)
• Ensures that all mature T cells can interact with MHC molecules (MHC restriction)
• Result: CD4⁺ or CD8⁺ single-positive T cells

Stage 3 — Negative Selection (Medulla)

• Thymocytes whose TCRs bind too strongly to self-antigens presented on MTECs and dendritic cells → clonal deletion (apoptosis)
• MTECs express the AIRE gene (autoimmune regulator), allowing expression of tissue-specific antigens (e.g., insulin, thyroid antigens) in the thymic medulla
• Eliminates self-reactive T cells → central tolerance = prevention of autoimmunity

"T cells undergo differentiation and a two-stage selection process (positive and negative selection) that leads to the development of immune tolerance by eliminating all T cells directed against the body's own tissues." — Histology: A Text and Atlas (Mescher)

Summary of the Thymus's Roles

Clinical Relevance