HEMATOPOIESIS 2

1. HEMATOPOIESIS 2 Doç. Dr. Gülderen Yanıkkaya Demirel

2. Objectives of this lecture • General information about the hematopoiesis • Hematopoietic stem cell • Cell maturation • Bone marrow Microenvironment • Regulatory mechanisms of hematopoiesis • Some examples of changes in hematopoiesis

5. Dr. Ewan Wingley, WAIMR sunumundan alıntılanmıştır.

7. Basic Features of HSC • Self renewal • Proliferation • Potential to differentiate • Differentiation • Lineage determination

8. HSC Properties • They do not carry lineage specific markers, such as • CD3, CD4, CD8 • B220 • Gr-1 • Mac-1 • TER119 • SCA-1 and CD34 are expressed • Myeloid cells mostly express c-kit (CD117).

9. PLASTICITY of HSCs Malcolm Moore, NEJM, 2000

11. Öncül HSC Çoğalan HSC Yönlenmiş Projenitör Olgun Hücreler CD34 Dizine özgün belirteçler ± ++ ++ - Replikasyon Telomeraz ± ++ ++ - Lansdorp P. Stem Cells, 18:1 – 30, 2000.

12. Germ line- telomeraz (+) HSC- telomeraz (+) Telomer uzunluğu Somatikhücreler- telomeraz (-) Kritik Telomer Uzunluğu Hücre Bölünme Sayısı Lansdorp P. Stem Cells, 18: 1 – 30 2000.

13. Proliferative potential differentiation Hematopoiesis

14. 10% 20% 10% 60% Normal Marrow Composition unidentified or disintegrated cells erythroid precursors Lymphocytes, monocytes granulocytes & precursors

15. Lifespan of blood cells • RBC 120 days • platelet 1 - 10 days • granulocytes circ : 9 hours tissue : days • lymphocyte circ : variable (hours to years) tissue : weeks to years

16. Anatomic Structure of Bone Marrow

18. Normal Marrow • myeloid to erythroid ratio = 3 : 1 • dominant myeloid cells myelocytes metamyelocytes granulocytes • dominant erythroid cells polychromatophilic normoblasts orthochromic normoblasts

20. CELLULAR MATURATION* Morphology • Cytoplasmic Maturation - Immature cell: intensely basophilic (blue) because of high RNA content. Loss of blue as cell matures. • Granules may appear as cell matures. They are non specific at first, take on specific characteristics as they mature. • Relative amount of cytoplasm increases as cell matures. • Nuclear Maturation • Immature nucleus is round or oval and large in proportion to rest of cell. • As cell matures, decreases in size and takes on varying shapes. • Nuclear chromatin changes from delicate and fine to coarse and clumped. • Staining properties change from reddish purple to bluish purple. • Nucleoli gradually disappear. *For myeloid cell line

21. CELLULAR MATURATION Immune Features • During Maturation - Signal transduction molecules effective in each and every step of differentiation of cells are different. - Cytokines, CSF, chemokines are different for each cell line. - Cell surface markers change during the course of differentiation.

22. HEMAPOIESIS REGULATORY MECHANISMS • Control of cytokine release by stromal cells (effect on the microenvironment) • Migration of cells from one microenvironment to other • Cytokine production by non stromal cells • Changes (increase or decrease) in numbers of cytokine receptors on the differentiating cells • Clearance of differentiating or differentiated cells by apoptosis (programmed cell death)

23. HEMAPOIESIS REGULATORY MECHANISMS • Control of cytokine release by stromal cells (effect on the microenvironment) • Migration of cells from one microenvironment to other • Cytokine production by non stromal cells • Changes (increase or decrease) in numbers of cytokine receptors on the differentiating cells • Clearance of differentiating or differentiated cells by apoptosis (programmed cell death)

24. What controls hematopoiesis ?

25. HEMAPOIESIS REGULATORY MECHANISMS • Control of cytokine release by stromal cells (effect on the microenvironment) • Migration of cells from one microenvironment to other • Cytokine production by non stromal cells • Changes (increase or decrease) in numbers of cytokine receptors on the differentiating cells • Clearance of differentiating or differentiated cells by apoptosis (programmed cell death)

29. HEMAPOIESIS REGULATORY MECHANISMS • Control of cytokine release by stromal cells (effect on the microenvironment) • Migration of cells from one microenvironment to other • Cytokine production by non stromal cells • Changes (increase or decrease) in numbers of cytokine receptors on the differentiating cells • Clearance of differentiating or differentiated cells by apoptosis (programmed cell death)

30. Immune Response

31. HEMAPOIESIS REGULATORY MECHANISMS • Control of cytokine release by stromal cells (effect on the microenvironment) • Migration of cells from one microenvironment to other • Cytokine production by non stromal cells • Changes (increase or decrease) in numbers of cytokine receptors on the differentiating cells • Clearance of differentiating or differentiated cells by apoptosis (programmed cell death)

32. Growth Factor Stromal Cell HSC Response Growth Factor Receptor Stromal Cell HSC No Response Stromal Cell HSC No Response

33. HEMAPOIESIS REGULATORY MECHANISMS • Control of cytokine release by stromal cells (effect on the microenvironment) • Migration of cells from one microenvironment to other • Cytokine production by non stromal cells • Changes (increase or decrease) in numbers of cytokine receptors on the differentiating cells • Clearance of differentiating or differentiated cells by apoptosis (programmed cell death)

41. B cell maturation - immunophenotype

42. T cell maturation - immunophenotype

43. Orkin, SH, Cell, 2008

44. Pronormoblast

45. Bazofilik Normoblast

46. Polikromatofilik Normoblast

47. Ortokromafilik Normoblast

48. Retikülosit

49. Erythrocyte Parameters in Blood Count Hematokrit Kadın %35-47 Erkek %40-52 Hemoglobin Kadın 12-16 gr/dl Erkek 13.5-17.5 gr/dl MCV 80-100 fl Retikülosit Sayısı %0.2-2.0