246. HSC, Hematopoiesis Flashcards
What is hematopoiesis? What are its two states?
H: the process for HSC (hematopoietic stem cells) to become mature blood cells, continuous throughout life
- Steady state: replaces cells lost to normal programmed cell death
- Stress state: increased proliferation of specific blood cell types in response to external challenges (bleeding, high altitude, infection)
What are the 3 main characteristics of HSCs?
- Pluripotent: differentiate into ANY mature blood cell (lymphocytes, granulocytes, monocytes, RBCs, platelets)
- Self-Renewing: proliferate and create daughter cells to maintain HSC pool
- Homing capability: transit the circulation but return home to bone marrow to differentiate/proliferate (live in sinusoids and home to endosteum for differentiation)
What are the 2 models for hematopoiesis?
- Instructive: “choice” made by HSC due to specific growth factor stimulation (stress response)
- Stochastic: “choice” made by ongoing subtle HSC programming due to undefined local factors in the niche (steady state response)
What are the differences between HSC, ESC (embryonic stem cells), and iPSC (induced pluripotent stem cells)?
HSC: pluripotent and self renewing for any mature BLOOD cells
ESC: derived from blastocyst inner cell mass, can be cultured under growth factor conditions to generate any specific cell types (including hematopoietic tissues)
iPSC: derived from any adult cell type, engineered to express proteins characteristic of primitive cells (Oct4, Sox2, c-myc, Klf4), de-differentiated to some pluripotency
warning: may generate benign tumors in vivo (teratoma)
What are the different locations of hematopoiesis throughout life?
- Yolk Sac
- Aorta, gonad, mesonephros
- Placenta
- Fetal Liver
- Bone Marrow (adult/post-natally)
What can pluripotent HSCs differentiate into? What are these end products?
- CLP (common lymphoid progenitor)
- B and T cells
- develop outside bone marrow niche - CMP (common myeloid progenitor)
- MEP (megakaryocyte erythroid progenitors) = RBCs and platelets
- GMP (granulocyte monocyte progenitors) = granulocytes, monocytes, eosinophils, basophils
What are the key events of Erythropoiesis?
- what stimulates erythropoiesis?
- what are clinical uses for erythropoiesis stim?
HSC > CMP > MEP > BFU-E (burst form) > CFU-E (colony form) > proerythroblast > RBC
- 5 days from proerythroblast to RBC
Over time:
- nucleus size decreases (and enucleates), chromatin aggregates
- cytoplasm changes from blue to orange (more Hb)
Erythropoietin: produced by kidney due to changes in blood O2 tension
- fx: interacts with Epo-R on MEP, stim proliferation of MEP (MEP to more MEPs), induce differentiation of MEP to RBC
- use: tx of anemia due to renal insufficiency or post-chemo-tx; may be useful in bone marrow dysfx syndromes (myelodysplastic syndromes, early plastic anemia, anemia of chronic disease)
Thrombopoiesis
- key events
- stimulator
- clinical uses
HSC > CMP > MEP > Megakaryocytes > multiple platelets
Key event: endomitosis - precursors develop from 2N = 4N = 8N == 128N by arresting and restarting mitosis
Thrombopoietin
- produced by hepatocytes
- fx: interacts with c-mpl receptor on MEP, induce differentiation of MEP to megakaryocyte, increase platelet production (late differentiation)
- use: not used clinically
Myelopoiesis
- key events
- stimulator
- clinical uses
HSC > CMP > GMP (granulocyte myeloid progenitor) > granulocyte (aka monocyte, PMN)
7-10 days of production time, nuclei condenses (less RNA), cytoplasm gets paler
Stimulators
- IL-3: produced by T cells, interacts with IL-3-r to prevent apoptosis in CMP (no differentiation, no clinical use)
- GM-CSF (granulocyte/monocyte colony stimulating factor): produced by T cells and endothelial cells and fibroblasts (reacts to enviro changes) to interact with GM-CSF-r to stim differentiation of CMP to GMP, antagonize apoptosis and increase proliferation of GMP, prime granulocytes for activation; used for shortening post-chemotx neutropenia (but many SE from stimulating immature progenitor)
- G-CSF (granulocyte colony stimulating factor): produced by T cells and endothelial cells and fibroblasts to interact with G-CSF-r on GMP to stimulate differentiation of GMP to PMN (with initial increase in proliferation of GMP), USED TO SHORTEN NEUTROPENIA Post-Chemo-Tx (does not improve morbidity/mortality) or to increase granulocytes in pts with Severe Congenital Neutropenia (SE: increases leukemia risk due to selection of mutated GCSF factors)
Cytokine Regulation of Hematopoiesis
- types used
- structure and function of each type
- examples of each type
All receptors: all transmembrane with EC ligand-binding and IC signaling
Class I cytokine receptors: no endogenous kinase activity (cannot phosphorylate other proteins, only dock proteins that can)
- structure: ligand binding causes dimerization and conf change, opens IC binding site for signaling proteins
- positive regulatory domains: increase proliferation, survival, differentiation
- negative regulatory domains: off signals (- fb)
- ex: Beta Common Chain (IL3-R, IL5-R, GM-CSF-R) - heterodimers all with same common chain (overlap in signaling effect) but unique alpha chain to confer specificity and other effects
- ex: Epo-R, G-CSF-R form homodimers specific for ligand interaction
Class III cytokine receptors: endogenous tyrosine kinase
- structure: ligand binds = dimerization = conf change = JUXTAMEMBRANE DOMAIN (IC) conf change activates signaling by unmasking kinase domain = kinase domain phosphorylates intermediates/activates signaling cascade
- ex: VEGF-R like (Flt3, PDFR-R, M-CSF, Kit, FGF)
Fanconi Anemia
- what is it
- manifestations
- tx
DNA repair defect: cannot repair protein cross-links = inability to produce adequate stress response
CM: early age bone marrow failure, Acute Myeloid Leukemia (AML) in adolescence, variable skeletal abnormalities (absent thumbs/radius)
[CONGENITAL]
TX:
- Stem cell tx, preferably before leukemia develops
- survivors develop Head/Neck or lung cancer later due to mutation
Dyskeratosis Congenita
- what is it
- manifestations
- tx
Telomere Defect: telomerase dysfx = shortened telomeres = similar changes seen with normal aging
CM: severe childhood presentation of bone marrow failure, abnormal skin/nails, leukoplakia (abnormal epithelial repair) progressing to head/neck cancers
[CONGENITAL]
Tx:
- stem cell tx
- nothing for other CPs
Shwachman-Diamond Syndrome
- what is it
- manifestations
- tx
Mutation in SDBS gene: unknown fx, may influence ribosome fx
CM: in childhood, bone marrow failure, exocrine pancreas failure, growth delay
[CONGENITAL]
tx:
- stem cell tx (bone marrow failure)
- insulin (exocrine pancreas)
Myelodysplastic Syndrome (MDS)
- what is it
- manifestations
- tx
Accumulation of mutations in HSC genome: hx of remote toxic chemical/radiation exposure; undefined inherited genetic abnormalities increasing susceptibility
CM: older adults, bone marrow failure and pancytopenia evolving over time, accumulation of chromosomal gains/losses, evolution to AML
[ACQUIRED]
Tx:
- stem cell tx in younger pts
- Nucleoside Analogues (5-azacytidine) delay AML (disadvantages rapidly proliferating cells)
- Chemotx ineffective for AML :(
Aplastic Anemia
- two main causes (which is most common?)
- manifestations
- tx
- Autoimmune: T-cell mediated (most common) - recognizes and destroys stem cell progenitors
- Acute HSC damage by drugs/high dose radiation
CM: pancytopenia with normal cell morphology and cytogenetics (ddx from MDS bc cells are NOT dysplastic), evolution to “empty marrow”
tx:
- immunosuppression (75% success rate): re-boot immune system to get rid of bad T cells
- Stem Cell Tx if unsuccessful or if caused by radiation/drug
