SM_246b: Stem Cells and Hematopoiesis

Question 1

Hematopoiesis is ____

Answer 1

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

Question 2

Hematopoietic stem cells are ____, ____, and have ____

Answer 2

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”

Question 3

Regulation of hematopoietic stem cells involves a choice between ____ and ____

Answer 3

Regulation of hematopoietic stem cells involves a choice between differentiation and proliferation

Question 4

Hematopoietic stem cell depletion results in ____

Answer 4

Hematopoietic stem cell depletion results in bone marrow failure

Question 5

Hematopoietic stem cell maintenance results in ____

Answer 5

Hematopoietic stem cell maintenance results in steady state production

Question 6

Hematopoietic stem cell expansion results in ____

Answer 6

Hematopoietic stem cell expansion results in stress production

Question 7

Embryonic stem cells are derived from ____ and then ____

Answer 7

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)

Question 8

Definitive hematopoiesis occurs in ___

Answer 8

Definitive hematopoiesis occurs in bone marrow in adult

Question 9

Pluripotent hematopoietic stem cells differentiate into ____ or ____

Answer 9

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)

Question 10

Hematopoietic stem cell differentiation results in ____ and ____

Answer 10

Hematopoietic stem cell differentiation results in loss of pluripotency (irreversible commitment) and loss of self-renewal (mitotic arrest in mature cells)

Question 11

Describe changes that occur in erythropoiesis

Answer 11

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

Question 12

___ is the major growth factor for RBC development

Answer 12

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

Question 13

Describe thrombopoietin

Answer 13

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)

Question 14

Myelopoiesis is ___

Answer 14

Myelopoiesis is granulocyte and monocyte development

Question 15

Granulopoiesis takes ___

Answer 15

Granulopoiesis takes 5-7 days

Question 16

Describe cytokines involved in granulocyte and monocyte differentiation

Answer 16

Cytokines involved in granulocyte and monocyte differentiation

• IL-3
• GM-CSF
• G-CSF
• M-CSF

Question 17

Describe IL-3

Answer 17

IL-3

• Produced by T cells
• Functions: interacts with IL-3-R, prevents apoptosis in CMP, does not induce differentiation
• Not useful clinically

Question 18

Describe GM-CSF

Answer 18

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

Question 19

Describe G-CSF

Answer 19

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

Question 20

Describe cytokine regulation of hematopoiesis

Answer 20

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

Question 21

Describe cytokine receptors involved in hematopoiesis

Answer 21

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

Question 22

Describe class I cytokine receptors

Answer 22

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

Question 23

Beta common chain receptors are ____ and form ____

Answer 23

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

Question 24

Hematopoietin is a ____ that forms ____

Answer 24

Hematopoietin is a class I cytokine receptor that forms homodimers that are specific for ligand interaction

• Examples: Epo-R, G-CSF-R

Question 25

Describe class III cytokine receptors

Answer 25

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

Question 26

Fanconi anemia results from a ___ defect

Answer 26

Fanconi anemia results from a DNA repair defect * Ineffective cross-link repair

Question 27

Fanconi anemia presents as \_\_\_\_, \_\_\_\_, and \_\_\_\_

Answer 27

Fanconi anemia presents as * Bone marrow failiure at an early age * Acute myeloid leukemia in adolescence * Variable skeletal abnormalities

Question 28

Dyskeratosis congenita results from a ___ defect

Answer 28

Dyskeratosis congenita results from a telomere defect * Shortened telomeres due to telomerase dysfunction * Similar changes seen with normal with aging

Question 29

Dyskeratosis congenita presents in ____ with \_\_\_\_, \_\_\_\_, and \_\_\_\_

Answer 29

Dyskeratosis congenita presents in childhood with bone marrow failure, abnormalitiies of skin and nails, and leukoplakia progressing to head / neck cancers

Question 30

Shwachman-Diamond syndrome results from \_\_\_

Answer 30

Shwachman-Diamond syndrome results from a mutation in the SDBS gene * Function unknown but may influence ribosome function

Question 31

Shwachman-Diamond syndrome presents in ____ with \_\_\_\_, \_\_\_\_, and \_\_\_\_

Answer 31

Shwachman-Diamond syndrome presents in childhood with bone marrow failure, exocrine pancreas failure, and growth delay

Question 32

Myelodysplastic syndrome results from \_\_\_\_

Answer 32

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

Question 33

Myelodysplastic syndrome presents in ____ with \_\_\_\_, \_\_\_\_, and \_\_\_\_

Answer 33

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

Question 34

Aplastic anemia results from ____ or \_\_\_\_

Answer 34

Aplastic anemia results from T-cell mediated autoimmune processes or acute hematopoietic stem cell damage by drugs / high dose radiation

Question 35

Aplastic anemia presents with \_\_\_\_, \_\_\_\_, and \_\_\_\_

Answer 35

Aplastic anemia presents with pancytopenia, normal cytogenetics / cell morphology, and evolution to empty marrow

Question 36

Hematopoietic stem cell transplantation requires \_\_\_\_

Answer 36

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)