Hematopoiesis Flashcards
1
Q
Basic requirements for hematopoiesis
A
- Stem cells and progenitor cells
- Appropriate microenvironment
- Hematopietic growth factors and interleukins
2
Q
Overview of hematopoiesis
A
- Hematopoietic stem cells (HSC)-> mulitpotent progenitor cells-> oligopotent progenitor cells (CLP, CMP-> MEP and GMP)-> lineage restricted progenitor cells (Mbl, Pro, PM, MB)-> specific cell type
- CLP (common lymphoid progenitor), CMP (common myeloid progenitor), MEP (Megakaryocyte/erythrocyte progenitor), GMP (Granulocyte/monocyte progenitor)
- Mbl (Myeloblast-> granulocytes), Pro (Pronormoblast-> erythrocytes), PM (Promonocyte-> monocyte), MB (Megakaryoblast-> megakaryocyte)
3
Q
HSC
A
- Can self-renew, a single cell can establish long-term hematopoiesis
- Ability to differentiate into progenitors of all lineages
- Most are in Go (quiescent) and undergo rapid proliferation when required (via GFs and signaling molecules)
- May be transplanted into HLA identical patients
4
Q
Progenitor cells
A
- Mulitpotent progenitor have short term self renewal capacity, but cannot repopulate indefinitely
- They give rise to CLP and CMP (common lymphoid or myeloid progenitors), which have no self-renewal ability
- The “common” progenitors give rise to the lineage restricted progenitors
- Lineage restricted progenitors (myeloblasts, pronormoblasts, ect) are responsive to more specific cytokines/ILs
5
Q
HSC transplants
A
- HSCs sources: bone marrow (BM), or mobilized peripheral blood and umbilical cord blood
- Allogenic: from someone else
- Autologous: from yourself
- Common uses of HSC replacement: after myeloablative Rx for cancer (most common), immunoRx for cancer, correction of immune/hematopoietic deficiency, genetic disorders, gene transfer (vehicle), Rx of autoimmune disease, induction of donor-specific tolerance after solid organ transplant
6
Q
Microenvironment of bone marrow
A
- HSC first arise simultaneously in yolk sac, placenta, and AGM regions in embryo
- Hematopoiesis then shifts to the liver in the fetus, then moves to the BM in urtero
- Microenvironment (ME) consists of vascular endothelium, fibroblasts, macrophages, and osteoblasts (collectively termed marrow stroma)
- Osteoblasts are key part of “stem cell niche”: region in BM where HSCs self-renew
- Stromal cells produce wide range of cytokines and ILs (GFs), and adhesion molecules
7
Q
Hematopoietic GFs
A
- 60-70 cytokines influence hematopoiesis, all are glycoproteins w/ multiple activities
- GFs that induce proliferation of a precursor to differentiate into a terminal progeny will often enhance the functionality of that progeny’s activity
- A cytokine may act on multiple lineages and cell types and their function may be additive or synergistic
8
Q
Granulocyte colony stimulating factor (GCSF)
A
- Made in monocytes, endothelial cells, fibroblasts, neutrophils in response to a variety of factors (IL1, TNG, IFNg, endotoxin, ect)
- Induces proliferation of granulocytes (increasing PMN count) and mobilization of stem cells into peripheral circulation
- Primes neutrophils to undergo oxidative metabolism
- Increases capability of neutrophils to mediate Ab-dependent cell mediated cytotoxicity
9
Q
Thrombopoiesis
A
- Platelets are most abundant cell in blood
- Production of megakaryocytes (Mk) under the influence of thrombopoietin (TPO), which is mostly made in liver (some in kidney)
- Inverse relationship btwn TPO levels and Mk/platelet levels
- Receptors on Mk and platelets bind TPO and degrade it, so when Mk/platelet levels are high TPO is low
- When Mk/platelet levels drop there is more TPO and more of the cells are made
- TPO regulates all stages of megakaryopoiesis
- Megakaryocytes squeeze btwn endothelial cells in the BM and shed off platelets by sticking part of themselves into the high pressure blood stream
10
Q
Erythropoiesis
A
- Controlled primarily by EPO (erythropoietin), which is made by the peritubular cells of the kidney
- Control of EPO production is based on tissue oxygenation, w/ peritubular cells serving as O2 sensor
- As O2 levels drop more peritubular cells are recruited, and HIF-1a (hypoxia-inducible factor) mRNA and protein levels are increased
- HIF-1a activates EPO gene transcription
- HIF-1a acts as the O2 sensor to increase EPO and erythropoiesis
11
Q
Functions of EPO
A
- EPO bring committed progenitor cells (MEP) into dividing pool
- It prevents apoptosis of these cells (via FasL)
- It speeds up maturation process of the RBC precursors
- Allowing early release of immature RBC precursors into blood (shift cells) by decreasing expression of receptors that are holding the cells in the BM
12
Q
Changes in EPO
A
- Inappropriately low levels of EPO: renal failure, chronic inflammatory state/infection, cancer
- Innapropriately high levels of EPO: polycystic kidney disease, cerebellar hemangiomas, cancer
- Appropriate increase of EPO: hypoxia due to altitude, lung disease
- Uses of EPO in medicine: renal failure, anemia caused by chronic disorders
13
Q
Retention of HSCs in bone marrow
A
- SDF1/CXCR4 interaction is necessary for retention of HSCs in bone marrow
- AMD3100 is a CXCR4 antagonist, and thus can mobilize HSCs from BM to peripheral blood
14
Q
Factors that influence maturation of progenitors
A
- MEP-> Mk due to TPO
- MEP-> Pronormoblast due to EPO
- GMP-> PM due to GM-CSF (granulocyte-macrophage colony stimulating factor)
- GMP-> Mbl due to G-CSF (granulocyte colony stimulating factor)
15
Q
Erythroid maturation
A
- Pronormoblast-> early normoblast-> intermediate normoblast-> late normoblast-> early reticulocyte (all in BM)
- Reticulocyte-> RBC (in blood)
- Last cell w/ nucleus: late normoblast
- Nucleus gets darker and more compact as the cell maturates (due to more RNA for Hb)
- Takes 5-6 days to mature in BM, RBCs last 120 days in blood
