SM_246b: Stem Cells and Hematopoiesis Flashcards
Hematopoiesis is ____
Hematopoiesis is the process for hematopoietic stem cells to become mature blood cells
- Sequential acquisition of lineage specific characteristics
- Results in production of all blood cell types
- Continuous process through the life of the organism
Hematopoietic stem cells are ____, ____, and have ____
Hematopoietic stem cells are pluripotent, self-renewing, and having homing capability
- Pluripotent: ability to differentiate into any of the mature blood cells
- Self-renewing: able to proliferate and create daughter cells to maintain hematopoietic stem cell pool
- Homing capability: occassionally transit circulation but able to identify bone marrow “niche”
Regulation of hematopoietic stem cells involves a choice between ____ and ____
Regulation of hematopoietic stem cells involves a choice between differentiation and proliferation
Hematopoietic stem cell depletion results in ____
Hematopoietic stem cell depletion results in bone marrow failure
Hematopoietic stem cell maintenance results in ____
Hematopoietic stem cell maintenance results in steady state production
Hematopoietic stem cell expansion results in ____
Hematopoietic stem cell expansion results in stress production
Embryonic stem cells are derived from ____ and then ____
Embryonic stem cells are derived from blastocyst inner cell mass and then cultured under growth factor conditions to generate specific cell types (such as hematopoietic tissues)
Definitive hematopoiesis occurs in ___
Definitive hematopoiesis occurs in bone marrow in adult
Pluripotent hematopoietic stem cells differentiate into ____ or ____
Pluripotent hematopoietic stem cells differentiate into common lymphoid progenitors or common myeloid progenitors
- Common lymphoid progenitors: B cells and T cells, development outside of bone marrow niche
- Common myeloid progenitors: megakaryocyte erythroid progenitors (RBCs and platelets), granulocyte monocyte progenitors (granulocytes / monocytes / basophils / eosinophils)
Hematopoietic stem cell differentiation results in ____ and ____
Hematopoietic stem cell differentiation results in loss of pluripotency (irreversible commitment) and loss of self-renewal (mitotic arrest in mature cells)
Describe changes that occur in erythropoiesis
Erythropoiesis
- Cytoplasm changes from blue to orange: decrease in RNA, increase in hemoglobin
- Nucleus becomes smaller
- Chromatin pattern becomes more aggregated
- Production time: 5 days
___ is the major growth factor for RBC development
Erythropoietin is the major growth factor for RBC development
- Produced by kidney in response to changes in blood O2 tension, decrease in renal failure resulting in anemia
- Function: interacts with Epo-R on megakaryocyte-erythryoid progenitor, stimulates proliferation on megakaryocyte-erythryoid progenitor, and induces differentiation of on megakaryocyte-erythryoid progenitor to RBC
Describe thrombopoietin
Thrombopoietin
- Produced by hepatocytes
- Functions: interacts with c-mpl receptor on megakaryocyte-erythryoid progenitor, induces differentiation of megakaryocyte-erythroid progenitor to megakaryocyte, increases platelet production (late differentiation)
Myelopoiesis is ___
Myelopoiesis is granulocyte and monocyte development
Granulopoiesis takes ___
Granulopoiesis takes 5-7 days
Describe cytokines involved in granulocyte and monocyte differentiation
Cytokines involved in granulocyte and monocyte differentiation
- IL-3
- GM-CSF
- G-CSF
- M-CSF
Describe IL-3
IL-3
- Produced by T cells
- Functions: interacts with IL-3-R, prevents apoptosis in CMP, does not induce differentiation
- Not useful clinically
Describe GM-CSF
GM-CSF
- Produced by T cells, endothelial cells, and fibroblasts
- Functions: interacts with GM-CSF-R, stimulates differentiation of CMP to GMP, antagonizes apoptosis and increases proliferation in GMP, primes granulocytes for activation
- Clinical use: shortens post-chemo neutropenia, has side effects
Describe G-CSF
G-CSF
- Produced by T-cells, endothelial cells, and fibroblasts
- Functions: interactions with G-CSF-R on GMP, stimulates differentiation of GMP to PMH, and initially increases proliferation of GMP
- Clinical uses: shortens neutropenia post chemo, increases granulocytes in patients with severe congenital neutropenia
Describe cytokine regulation of hematopoiesis
Cytokine regulation of hematopoiesis
- Hematopoietic cytokines (growth factors): complex networks, different combinations have different results
- Some common usage between lineage: earlier in differentiation, more specific cytokines required as each lineage differentiates
Describe cytokine receptors involved in hematopoiesis
Cytokine receptors involved in hematopoiesis
- Three domains: extracellular, transmembrane, intercellular
- Ligand binding: activation of signaling cascades
- Class I cytokine receptors: no endogenous kinase activity
- Class III cytokine receptors: tyrosine kinase domains
Describe class I cytokine receptors
Class I cytokine receptors
- Extracellular domain: ligand binding causes dimerization, induces conformational change
- Intercellular domain: Src homology domains are binding site for signaling proteins, positive regulatory domains increase proliferation / survival / differentiation, negative regulatory domains are off signals
Beta common chain receptors are ____ and form ____
Beta common chain receptors are class I cytokine receptors and form heterodimers
- Same beta chain, different alpha chain
- Examples: IL3-R, IL5-R, GM-CSF-R
Hematopoietin is a ____ that forms ____
Hematopoietin is a class I cytokine receptor that forms homodimers that are specific for ligand interaction
- Examples: Epo-R, G-CSF-R
Describe class III cytokine receptors
Class III cytokine receptors
- Extracelliular domain: ligand binding causes dimerization, induces conformational change
- Intercellular domain: juxtamembrane domain activates signaling, kinase domains phosphorylate intermediates and activate signaling cascades
- VEGF-R like relevant to hematopoiesis: Flt3, PDFR-R, M-CSF, Kit, FGF
Fanconi anemia results from a ___ defect
Fanconi anemia results from a DNA repair defect
- Ineffective cross-link repair
Fanconi anemia presents as ____, ____, and ____
Fanconi anemia presents as
- Bone marrow failiure at an early age
- Acute myeloid leukemia in adolescence
- Variable skeletal abnormalities
Dyskeratosis congenita results from a ___ defect
Dyskeratosis congenita results from a telomere defect
- Shortened telomeres due to telomerase dysfunction
- Similar changes seen with normal with aging
Dyskeratosis congenita presents in ____ with ____, ____, and ____
Dyskeratosis congenita presents in childhood with bone marrow failure, abnormalitiies of skin and nails, and leukoplakia progressing to head / neck cancers
Shwachman-Diamond syndrome results from ___
Shwachman-Diamond syndrome results from a mutation in the SDBS gene
- Function unknown but may influence ribosome function
Shwachman-Diamond syndrome presents in ____ with ____, ____, and ____
Shwachman-Diamond syndrome presents in childhood with bone marrow failure, exocrine pancreas failure, and growth delay
Myelodysplastic syndrome results from ____
Myelodysplastic syndrome results from an accumulation of mutations in the hematopoietic stem cell genome
- Often history of remote toxic chemical / radiation exposure
- Undefined inherited genetic abnormalities
Myelodysplastic syndrome presents in ____ with ____, ____, and ____
Myelodysplastic syndrome presents in older adults with bone marrow failure / pancytopenia that evolves over time, accumulation of chromosomal gains / losses, and evolution to acute myeloid leukemia
Aplastic anemia results from ____ or ____
Aplastic anemia results from T-cell mediated autoimmune processes or acute hematopoietic stem cell damage by drugs / high dose radiation
Aplastic anemia presents with ____, ____, and ____
Aplastic anemia presents with pancytopenia, normal cytogenetics / cell morphology, and evolution to empty marrow
Hematopoietic stem cell transplantation requires ____
Hematopoietic stem cell transplantation requires close matching
- Ideally sibling donor, HLA matched unrelated donor possible for younger patients
- Complications: graft failure / lack of engraftment, graft vs host disease (transplanted marrow rejects recipient)
