Hematopoiesis

Tissue Homeostasis

• Maintain sufficient number of cells to carry out functions of an organism

• Dictates by cytokines (activate & inhibit)

Commitment

• Two cells derived from the same precursor and take a diverge route of developments

• Cell is restricted to a specific lineage

• Still undifferentiated morphologically

Maturation

• Final development of differentiated cells into functional form

• Begins with commitment and ends when cell has all its characteristics

Hematopoietic Cells Hierchachy

• Stem cells (HSC): 0.5% of total precursor cells, can differentiate as any blood cells, stays in quiescent phase, can self-renew

• Progenitor cells (HPC): 3% of total precursor cells, rapidly proliferate but short-lived before differentiating. Lack self-renewal (produce cells that are more lineage-restricted)

Stem Cell Niches

• Where HSC reside, provide both a physical anchor for HSC and factors that regulate number and function of HSC

• 2 stem cell niches

  • Osteoblastic niche: support & maintain HSC quiescence and renewal

  • Vascular niche: signals for proliferation and differentiation

Progenitor Cells

• Correlates with down-regulation of HSC genes and activate epigenetic regulation (lineage-specific genes)

• Express lineage-specific transcription factors

• No self-renewal ability

• Not morphologically identifiable but functionally defined based on mature progeny that are produced

• Mitotically more active

• 3% of nucleated hematopoietic precursor cells

Maturing Cells

• 95% of hematopoietic precursor cells due to proliferation & amplification

• Recognizable nuclear and cytoplasmic that can be used to classify lineage

• Earliest recognizable lineage is blast: myeloblast, lymphoblast, megakaryoblast

Cytokines/Hematopoietic GF

• Glycoprotein that govern hematopoietic precursor cell survival, self-renewal, proliferation & differentiation

• Colony stimulating factors (CSF) is a subset of it

• Produced by different cells except EPO (kidney)

• Interact with membrane receptors

Early-Acting (Multilineage) GF

• Stem-cell factor/mast cell growth factor (SCF/MSGF) and Flt3 ligand (FL)

• SCF promotes HSC and mast cell self-renewal

• Flt3 ligand expands early HPC and inhibit apoptosis

Later-Acting (Lineage-Restricted) GF

• Stimulate committed progenitor cells to differentiate

• EPO, TPO, G-CSF (granulocytes), M-CSF (monocytes)

Cytokine Sequence

1. Cytokine binds to membrane receptor

2. Signal transduction

3. Nuclear signaling to recruit TF

4. Gene activation/suppression

5. Cell response

Phosphorylation

• Intrinsic kinase activity (receptor is a kinase)

• Type RTK, RSK, PTP

Protein Tyrosine Kinases (PTK)

• No intrinsic kinase activity (receptor does not have kinase, recruits separate kinase)

• Most hematopoietic receptors signal through PTK using JAK

Nuclear Transcription Factors

• Establish pattern of gene expression associated with lineage differentiation

• Can activate/suppress genes

• Blood cancers occur due to mutations

Hematopoietic Microenvironment (HM)

• Cellular components: stromal & accessory cells. Secrete GF, negative regulators, cytokines

• Extracellular matrix: anchor HSC and HPC, and growth-regulatory proteins

HM Niches

• BM niche: ligand receptors bind HSC

• Stem cell niche: stromal cells produces factors that restrain HSC differentiation

• Lymphoid niche: arrange immature B cells closer to endosteal surface, differentiated B cells near endothelial cells

• Erythroid niche: erythroblastic islands

• Megakaryocyte niche: near sinusoidal endothelial cells, release platelets into bloodstream