HEMATOPOESIS Semmelweis University, Faculty of Medicine 1st year, 1st semester Department of Human Morphology and Developmental Biology Katalin Kocsis 13/11/2013 14/11/2013

What are stem cells? Stem cells are unspecialized cells that have two defining properties: the ability to differentiate into other cells and the ability to self-regenerate. The three broad categories of stem cells are: embryonic stem cells, derived from blastocysts, adult stem cells, which are found in adult tissues, and cord blood stem cells, which are found in the umbilical cord. Stem cells of the adult tissues are tissue specific: pl. hemopoetic, nervous, muscle stem cells

Totipotent stem cells Pluripotens (embryonic) stem cells

Potency of the stem cell Totipotens stem cells are produced from the fusion of an egg and sperm cell. Cells produced by the first few divisions of the fertilized egg are also totipotent. These cells can differentiate into embryonic and extraembryonic cell types. Pluripotent stem cells are the descendants of totipotent cells and can differentiate into cells derived from any of the three germ layers. Multipotent stem cells can produce only cells of a closely related family of cells (e.g. hematopoietic stem cells differentiate into red blood cells, white blood cells, platelets, etc.). Unipotent cells can produce only one cell type, but have the property of self-renewal which distinguishes them from non-stem cells.

Hematopoietic stem cells generate a hierarchy of differentiation. Multipotent stem cells reproduce to give rise to the myeloid cells (the erythrocytes (RBC) and the leukocytes (WBC) - eosinophils, neutrophils, basophils, monocytes and megakaryotes) and the lymphoid cells (B and T lymphocytes). Initially multipotent, the stem cell first becomes committed to either the lymphoid or myeloid lineages. This is followed by rounds of replication and further commitment to give the final 8 cell types. This occurs in the bone marrow and is regulated by growth factors and cytokines.

Current hypothesis about the colonisation of hematopoietic organs during embryonic development stages of hematopoesis: mesoblastic hepatolienal myeloid 7

Hematopoiesis and vasculogenesis closely linked -- spatially and temporally -- during embryonic development The hemangioblast Hypothetical common progenitor for hematopoietic and vascular endothelial cells hematopoietic endothelial

Yolk sac primitive hematopoesis Figure 13-1 A, Drawing illustrating the formation of hemangioblastic aggregates and their differentiation into hematopoietic stem cells and endothelial precursor cells within blood islands. Blood islands subsequently form both endothelial cells and primitive erythrocytes. B, Expression of Vegfr2 mRNA, an early marker for hemangioblastic aggregates, within the yolk sac wall of a 15-somite avian embryo. As the blood islands develop, endothelial cells retain Vegfr2 expression, whereas hematopoietic stem cells progressively lose it. 9

Yolk sac primitive hematopoesis Kessel és Fabian, 1985 mesoderm blood islands blood cells and vessels

Intraembryonic hematopoesis AGM region Figure 13-3 A second source of hematopoietic stem cells arises within the splanchnic mesoderm surrounding the aortic, gonad, and mesonephric region (AGM). These cells temporarily reside in the ventral floor of the dorsal aortic of this region. A, In humans at about day 27, a small number of hematopoietic stem cells (in red) reside and adhere to the dorsal aorta near the origin of the vitelline artery in the umbilical region. B, By day 30, the number of hematopoietic stem cells expands to several thousand. C, By day 36, hematopoietic stem cells expand to reside in the ventral floor of the dorsal aorta along almost the entire length of the AGM, and extending into the vitelline artery. By day 40, hematopoietic stem cells are no longer detected in the dorsal aorta. 12

Development of the circulatory system

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red bone marrow (spongy bone, long bone): stroma (reticulum cells, adipocytes, macrophages) cells of hematopoesis sinusoid (temporarily discontinuus endothel)

EPO (erythropoietin) (hypoxia) B12 (C, B6) vitamin iron, kobalt erythropoesis EPO (erythropoietin) (hypoxia) B12 (C, B6) vitamin iron, kobalt tiroxin, GM-CSF, IL-3, IL-4, stem cell faktor 8 day (160 million/minute) (normoblast)

thrombopoesis thrombopoietin 4-6000 platelet

granulocytopoesis 10 days monocytopoesis 1 day MPS (mononuclear phagocyte system) (tissue macrophages)

References: Röhlich Pál : Szövettan (SE) Gergely János és Erdei Anna által szerkesztett Immunbiológia (ELTE) Zboray Géza: A keringési szervek (ELTE jegyzet) Molecular biology of the cell, 5. edition Alberts et al. Molecular cell biology, Lodish et al.