경희대학교 의과대학·의학전문대학원

혈액학 서론

조혈 및 혈구생성기관

경희의대 종양혈액내과

조경삼

Stem Cell

• A cell with a unique capacity to produce unaltered daughter cells (self renewal) and to generate

Resident stem cell : skin, intestine, blood etc.

Cultured stem cell

Embryonic stem cell Fetal stem cell

Adult stem cell _{EC: embryonic carcinoma cell}

EG: embryonic germ ES: embryonic stem cell GS: germline stem

maGSC: multipotent adult germline stem MAPC: multipotent adult stem MS: mesenchymal stem

NS: neural stem

SSC: spermatogonial stem TS: trophoblast stem

USSC: unristricted somatic stem XEN: extraembryonic endoderm

Blood cells

• Cellular element of blood

– RBC: oxygen delivery

– WBC: host defense (bacteria) – Platelet: hemostasis

• Survival time in blood

– RBC: 120 days

– Granulocyte: 6-8 h; days in tissue

– Monocyte(macrophage): weeks to years

– Platelet: 10 days

– Lymphocyte: variable, hours up to several years

Hematopoiesis(

조혈 )

• Formation of blood cells

– RBC: tissue oxygen level

– WBC: noxious foreign stimuli (bacteria)

– Platelet: blood loss, tissue damage, platelet deficiency

• Over 500 billion cells per day

– RBC: 2 billion/Kg

– Platelet: 7 billion/Kg

Extramedullary hematopoiesis

(원능줄기세포 )

Progenitor cell (전구세포 )

Peritubular capillary lining cell, hepatocyte

(Half clearance time: 6 – 9 hr, 10 – 25 U/L)

20 회의 세포분열 : 106 성숙세포

적혈구 : 5 일 혈소판 : 7 일

HSC(hematopoietic stem cell)

• 0.01% of the bone marrow

• Marrow failure: granulocyte --- platelet---- RBC • Radioprotection in irradiated animal

• LTRC: long-term multilineage reconstitution • Formation of CFU-s

• Stem cell purification:

– physical properties: density centrifugation,

countercurrent elutriation

– Cell surface antigen: CD34, Hoechst 33342, Rh123

Hematopoietic

microenvironment

• Specific positional effect: product of microenvironment

• adipocytes, fibroblastoid cells, reticulo-endotheloid cells,

macrophages, T-cells

• Cell adhesion molecules, cytokines

• Extracellular matrix: collagens, laminin, fibronectin, proteoglycan

Cytokine regulation

• Stem cell factor, flt3 ligand

• IL-6, IL-11, IL-12, Tpo, G-CSF

• IL-3, IL-4, GM-CSF

• Maturing cells---late-acting

lineage-specific factors

– Epo, Tpo,

Sources of cytokines

• SCF, SF(steel factor): T lymphocytes

• GM-CSF, IL-3: T cells, monocytes,

fibroblasts, endothelial cells • G-CSF, M-CSF: monocytes, fibroblasts,

endothelial cells

• Epo: kidney, liver

• IL-5: T lymphocytes

• IL-11: fibroblasts, endothelial cells

hematopoietic cell growth

inhibitors

• IFN-alpha, beta, gamma, TNF-alpha

• Macrophage inflammatory protien 1alpha

• Prostaglandins, lactoferrin, H ferritin

Clinical implications of stem cell biology

• Diagnosis of hematologic diseases

• Bone marrow transplantation

• Gene therapy

• Therapeutic use of hematopoietic growth

Diagnosis

• Detection of specific mutations in populations and famillies at risk:

– carrier detection of sickle cell anemia

– estimation of specific-thalassemia mutations in population • Prenatal diagnosis of disease:

– beta thalassemia, sickle cell anemia • Detection of MRD:

– t(14;18), t(9;22), t(15;17), ARG rearrangements • Detection of clonality:

– ARG rearrangements

• Distinguishing genotypes of hematopoietic cells: – assessment of host/donor cell after BMT

Clonal origin of hematopoietic

malignancies

• Clonal immunoglobulin gene rearrangement • T cell receptor gene rearrangement

• Gene translocation

• Glucose-6phosphate dehydrogenase isoenzyme pattern

Bone marrow transplantation

• Autologous BMT:

– high dose chemotheray – tumor cell contamination

• Allogeneic BMT:

– GVHD – GVT

• PBSCT

HGF

• Erythropoiesis stimulating agent : Epo

• Thrombopoiesis stimulating agents :

– Tpo

– Second generation : Romiplostim, Eltrombopag • Leucopoiesis stimulating agents

– G-CSF, GM-CSF

• neutropenia • mobilization

• bone pain, rash fever, fatigue, anorexia, phlebitis, thrombosis,

capillary leak syndrome

Hematologic Diseases

• RBC

• WBC

• Platelet

• Bone marrow (stem cell)

• Coagulation factors

• Stem cell transplantation

• Transfusion

Erythroid

• Anemia

– Production defect – Destruction – Loss – Functional defect

• Erythrocytosis

– Primary – Secondary

WBC

• Leucocytosis

– Primary – Secondary

• Leucopenia

– Neutropenia – Lymphopenia

• Functional defect

Platelets

• Thrombocytosis

– Primary – Secondary

• Thrombocytopenia

– Production – Destruction

• Functional defects

Bone marrow (Stem cell)

• Primary

– Clonal disease

• Malignant : myeloid, lymphoid • Non-malignant : – Non-clonal

• Secondary

– Drug – Myelophthisia – Idiopathic

Others

• Coagulation factors – Deficiency : • Congenital • Acquired – Thrombosis

• Stem cell transplantation

– Allogeneic – Autologous