Study Notes on Hematopoiesis

HEMATOPOIESIS

Objectives

• Understand haemopoiesis and the types
• Know where (sites) haemopoiesis occurs in the body
• Discuss the bone marrow and its role in haemopoiesis
• Know what haemopoietic stem cells are and their features
• Learn about haemopoietic growth factors and their role in haemopoiesis

Definition of Hematopoiesis

• Hematopoiesis is the process of formation, development, and differentiation of the formed elements of blood.
• This process originates from hematopoietic stem cells (HSCs).
• Hematopoietic stem cells are characterized by:
  • Ability to self-renew and differentiate into all types of mature blood cell lineages.
  • Capability to rescue lethally irradiated hosts by reconstituting the entire repertoire of hematopoietic cells in recipients.

Hematopoietic Stem Cells (HSCs)

• Rarity of HSCs: Occurs at a frequency of 1 stem cell per 10,000 to 100,000 bone marrow (BM) cells.
• Steady State: HSCs are typically quiescent (noncycling), with only a fraction entering the cell cycle to proliferate and form differentiated progenitors.
• Response to Stress: In cases of hematopoietic stress (e.g., infections, acute bleeding, or chemotherapy), HSCs proliferate extensively.
• Regulation: Self-renewal and differentiation processes are tightly regulated, maintaining homeostasis. Historical deregulation can lead to myeloproliferative diseases (e.g., acute myeloid leukemia) or bone marrow failure syndromes (e.g., aplastic anemia).

Sites of Haemopoiesis

• Embryonic Phase:
  • 0–2 months: Occurs primarily in the yolk sac (primitive hematopoiesis).
  • 2–7 months: In fetal liver and spleen.
  • 5–9 months: In bone marrow as definitive hematopoiesis begins.
• Infants: Hematopoiesis occurs in all bones.
• Adults: Primarily occurs in:
  • Vertebrae
  • Sternum
  • Skull
  • Sacrum
  • Pelvis
  • Proximal ends of femur and humerus

Development of Hematopoiesis

• Hematopoietic development is conserved across mammals, originating from mesodermal tissues.
• During gastrulation, mesoderm is induced by prospective endoderm and patterned along the dorsal-ventral axis.
• Key Proteins Involved:
  • Bone morphogenetic proteins (BMPs)
  • Hedgehog (Hh) proteins
• The ventral mesoderm cells migrate to the yolk sac, generating the first wave of hematopoiesis (primitive hematopoiesis) characterized by large nucleated erythroid cells expressing embryonic hemoglobin.
• After the primitive wave, definitive hematopoiesis occurs in the aortic-gonad-mesonephros (AGM) region, where HSCs expand and migrate to the fetal liver and spleen to generate all hematopoietic cell lineages.

Origin of Hematopoietic Stem Cells

• The origin of the HSCs that give rise to definitive hematopoiesis remains unclear, but evidence suggests they derive from specialized endothelial cells in the dorsal aorta (referred to as hemogenic endothelium).
• During late fetal stages, HSCs migrate further to bone marrow and thymus.
• The migratory nature of HSCs during development explains their presence in adult non-hematopoietic tissues and their capacity to resume hematopoietic properties in bone marrow.

Ontogeny of Hematopoiesis

• Children to Teenage Years: Hematopoiesis occurs across all bones.
• Gradual Decrease: Decreases in the shafts of long bones with age.
• Ages 18-20: Hematopoiesis shifts to specific sites: sternum, ribs, pelvis, vertebrae, and skull.
• Post Age 40: Less area in these sites is available for hematopoiesis.

Cellularity of Hematopoiesis Sites

• During various fetal months, hematopoiesis occurs at different sites with varying cellularity percentages, highlighting:
  • Yolk sac
  • Spleen
  • Liver
  • Bone marrow
  • Femur, vertebra, sternum, tibia, rib, lymph nodes
  • Chart depicts cellularity percentages from 0%, 20%, to 100% over life stages (fetal months to age in years).

Medullary and Extramedullary Hematopoiesis

• Medullary Hematopoiesis: Occurs primarily in the red marrow of bones:

  • In fetuses after 5 months of gestation
  • Throughout life from birth to adulthood.

• Extramedullary Hematopoiesis: Occurs in tissues other than the bone marrow, typically post-birth only in diseases where medullary hematopoiesis is compromised (e.g., myelofibrosis):

  • Non-BM Hematopoietic Tissues: Yolk sac, liver, spleen, lymph nodes, thymus (crucial for T-cell maturation).
  • Indicative conditions include hepatomegaly, splenomegaly, or hepatosplenomegaly.

Bone Marrow Microenvironment

• The bone marrow microenvironment includes:
  • Blood Vessels and Stromal Cells: Adipocytes, fibroblasts, endothelial cells, and macrophages.
  • Extracellular Matrix Components: Collagen, glycoproteins (fibronectin and thrombospondin), glycosaminoglycans (hyaluronic acid, chondroitin derivatives).
• This environment is vital for stem cell survival, self-renewal, and differentiation.

Characteristics of Stem Cells

• Stem Cell Definition: Defined by self-maintenance and the ability to produce multiple cell types.
• Self-Renewal: The characteristic of stem cells to continuously generate identical daughter cells without differentiation.
• Asymmetry in Stem Cells: In each division, there's generally one cell that remains a stem cell while the other differentiates or undergoes apoptosis.

Types of Stem Cells

• Totipotent Stem Cells: Can develop into any cell type, including extra-embryonic tissues (e.g., placental tissues).
• Pluripotent Stem Cells: Can give rise to any body cells except those of extra-embryonic membranes. Induced pluripotent stem cells (iPS) can be created from mature cells, providing tools for basic biology and potential cell therapies.
• Multipotent Stem Cells: Such as hematopoietic stem cells of bone marrow, capable of giving rise to multiple cell types but restricted to a specific tissue (e.g., blood). Commonly found in adults for tissue repair.

Hematopoietic Growth Factors

• Definition: Glycoprotein hormones regulating proliferation and differentiation of hematopoietic progenitors, impacting various stages of hematopoiesis.
• Source: Most growth factors are produced by stromal cells in the bone marrow, except erythropoietin and thrombopoietin.
• Growth factors include cytokines that pass messages between cells to promote differentiation and activate signaling pathways.

Regulation of Hematopoiesis

• Stem Cell and Progenitor Interaction: Hematopoiesis begins with stem cell divisions, where one cell renews while the other commits to differentiation.
• Transcription Factors: Different transcription factors regulate stem cell survival and differentiation towards specific lineages. The selection of which lineage to differentiate into can depend on intrinsic and extrinsic signals.

Important Growth Factors in Hematopoiesis

• Colony-Stimulating Factors (CSFs): Act on multipotential progenitor cells, guiding differentiation into specific blood lineages.
• Interleukins: Various interleukins support the maturation of different blood cell lineages, including eosinophils, granulocytes, and macrophages.

Major Growth Factors Table

Cell Death in Hematopoiesis

• Apoptosis: Programmed cell death is important for balance and turnover within hematopoietic populations. It is characterized by:
  • Cell shrinkage
  • Condensation of chromatin
  • Fragmentation of DNA
• Necrosis: Occurs due to extreme insults, representing a failure in homeostasis.

Comparison of Apoptosis and Necrosis

Physiological Cell Turnover

• An adult human loses approximately $10^{11}$ cells per day, predominantly from skin, intestinal, and hematopoietic tissues.
• Physiologic death must balance with the generation of new cells to maintain homeostasis, with specific mechanisms for clearance of apoptotic cells to avoid inflammation.

Key Terms to Know

• Self-Renewal: The ability of stem cells to generate identical daughter cells.
• Potentiality: The capacity to differentiate into various cell types.
• Pluripotent: Stem cells that can become any blood cell type.
• Multipotent: Stem cells that can become one among several blood cell types.
• Unipotent (Committed): Precursor and mature cells that can only develop into one lineage.
• Differentiation: The process by which less specialized cells become more specialized.
• Commitment: Cells limited to progression in a specific lineage.
• Maturation: The final development stages of cells into their mature forms suitable for functioning in circulation or tissues.
• Multi-lineage differentiation: HSCs producing diverse hematopoietic cells, specifically CLPs (common lymphoid progenitors) and CMPs (common myeloid progenitors).

Summary

Hematopoiesis is a vital biological process with complex regulation involving various stem cell types, growth factors, and influential external signals. Understanding the intricacies of this process has deep implications for regenerative medicine and understanding diseases such as leukemia and anemia.