혈액학 서론
경희의대 종양혈액내과
조경삼
Stem Cell (
줄기세포 , 모세포 )
• A cell with a unique capacity to produce unaltered
daughter cells (
self renewal
) and to generate
specialized cell types (
potency
) :
자기복제 , 분화
Symmetrical or Asymmetrical
전능
원능
• Stem cells as therapy (either to replace cell lines that have been lost or destroyed, or to modify the behavior of other cells [mesenchymal stem cell]) :
•Stem cells as targets of drug therapy
• Stem cells to generate differentiated tissue for in vitro study of disease models for drug development
Challenges in clinical use of stem cell
• Ethical problems :
– Embryonic stem cell
– iPS (induced pluripotent stem cell) – Adult stem cell (multipotent)
• 임상적용의 필요 조건 – 충분한 세포수 확보 – 필요한 세포로의 분화력 – 충분한 기간 동안의 기능유지 ( 생존력 ) – 숙주 조직과의 통합 조정력 – 해로운 영향력 배제 : teratoma, malignancy
HSC(hematopoietic stem cell)
• 0.005% of the bone marrow cells CD34+ cell : 2 – 5%
• Stem cell -- pluripotent cell -- progenitor cell • 실험적 근거
– Radioprotection in irradiated animal
– LTRC: long-term multilineage reconstitution – Formation of CFU-s
• 임상 적용
– Stem cell transplantation
– Plerixfor (Mozobil) : CXCR4 antagonist Stem cell mobilization in
Identification of stem and progenitor cells
• 중간 크기 정도의 림프구 모양
• Functional assay or surface antigenic
characteristics
– In vitro assays : LTC-IC; CAFC; HPP-CFC;
CFU-GEMM
– Cell surface antigenic markers :
• CD34+, CD38-, Thy-1+, CD133+, c-kit+, CD33-, Lin-,
HLA-DR-– Rhodamine 123 (Rh-123-low), Hoechst 33342,
Extramedullary hematopoiesis BM aspiration and biopsy
BM anatomy and microenvironment
• Hematopoietic stem cell require cellular and soluble growth factor support
• Cellular component : surrounding bone, stromal cells and
microenvironment
• Microenvironment : a vast network of vascular channels or sinusoids between which float fronds of hematopoietic cells, including fat cells.
• Stromal cells : fibroblastoid cells, endothelial cells, and macrophages; these cells provide cell-cell contact support to HSC and growth factors
• Stem cell niche in BM :
– Endosteal niche : self-renewal
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
Blood cells
• 혈액세포
– RBC: oxygen delivery
– WBC: host defense (bacteria) – Platelet: hemostasis
• 수명
– 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 )
• 조혈 자극
– RBC: tissue oxygen level
– WBC: noxious foreign stimuli (bacteria)
– Platelet: blood loss, tissue damage, platelet deficiency
• 생산량 : Over 500 billion cells per day
– RBC: 2 billion/Kg ; 10 billion/hr
– Platelet: 7 billion/Kg
– Neutrophil: 0.85 billion/Kg
• 성숙 조혈세포 Erythrocyte, neutrophil, eosinophil, basophil, monocyte, B cell, T cell, NK cell, dendritic cell
Clinical implications of stem cell biology
• Diagnosis of hematologic diseases
• Stem cell transplantation
• Gene therapy
• Therapeutic use of hematopoietic growth
Diagnosis (molecular biology)
• 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 and lineage :
– ARG rearrangements, cell surface marker
• Distinguishing genotypes of hematopoietic cells:
Detection of MRD
(CR : complete remission)
• Hematologic : morphologic
• Cytogenetic :
– chromosome analysis
– FISH
• Cell surface marker :
– Flow cytometry (multi-color)
• Molecular biology :
Stem cell transplantation
• Autologous SCT:
– high dose chemotheray
– tumor cell contamination
• Allogeneic SCT: Immunotherapy
– 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
• Others :
– II-3, IL-6, IL-1, Pixy-321(IL-3+GM-CSF) – In vitro expansion of HSC
Clinical use of HGF
• Transient bone marrow failure following chemotherapy • Hematopoietic stem cell and progenitor cell mobilization • Recovery from hematopoietic cell transplantation
• Myelodysplastic syndrome • Aplastic anemia
• Some forms of neutropenia
• Inherited bone marrow failure syndromes • HIV infection-associated neutropenia
• Chronic anemias (eg, renal failure, prematurity,
chronic disease/inflammation, HIV infection) • Reducing the need for perioperative blood transfus
Potential toxicities of the recombinant HGFs
• Transient leukopenia
• Systemic reactions (eg, flu-like symptoms,
capillary leak, hypertension, thrombosis)
• Production of deleterious neutralizing antibodies
• Possible stimulation of malignancy
• Possible enhancement of HIV replication
Field of Hematology
• RBC
• WBC
• Platelet
• Bone marrow (stem cell)
• Coagulation factors
• Stem cell transplantation
• Transfusion
Erythroid
• Anemia
– Production defect : iron deficiency anemia
– Destruction : hemolytic anemia
– Loss : hemorrhage
• Erythrocytosis
– Primary : polycythemia vera : MPN
– Secondary erythrocytosis
WBC
• Leucocytosis
– Primary : MPN, leukemia
– Secondary : leukemoid reaction
• Leucopenia
– Primary : AA, MDS
– Secondary : drug, infection
• Functional defect
– Congenital
– Acquired
Platelets
• Thrombocytosis
– Primary : MPN
– Secondary : infection, Fe deficiency
• Thrombocytopenia
– Production : aplastic anemia
– Destruction : ITP, DIC
• Functional defects :
– Congenital : thrombasthenia
– Acquired
Bone marrow (Stem cell)
• Tumors of hematopoietic and lymphoid tissues
(WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues (2008))
– Myeloid neoplasm
– Acute leukemia of ambiguous lineage
– Lymphoid neoplasm
– Histiocytic and dendritic cell neoplasm
• Hypoplastic anemia
– Idiopathic – Drug
