- HEMATOPOIESIS

The term hematopoiesis refers to the formation and development of the cells of the blood. In humans, this process begins in the yolk sac in the first weeks of embryonic development. By the third month of gestation, stem cells migrate to the fetal liver and then to the spleen (between 3-7 months gestation these two organs play a major hempatopoietic role).

Next, the bone marrow becomes the major hematopoietic organ and hematopoiesis ceases in the liver and spleen.

Every functional specialized mature blood cell is derived from a common stem cell. These stem cells are therefore, PLURIPOTENT.

It has been estimated that there is approximately 1 stem cell per 10⁴ bone marrow cells. These stem cells represent a self-renewing population of cells.  These cells also must have the potential to differentiate and to become committed to a particular blood cell lineage.

Due to the low frequency of these cells and the inability to culture these cells in vitro, stem cells have been very difficult to study.

However, in vivo studies in mice have shown:

Mouse with lethal irradiation (950rads)-------->  Death in 10 days.

If mouse is infused with only 10⁴-10⁵ bone marrow cells from a syngeneic donor, the hematopoietic system can be completely restored.  Therefore, there must be at least one stem cell in a population of bone marrow cells of this size.  A single stem cell is capable of completely restoring the hematopoietic process.

Initial differentiation of pluripotent stem cells will be allong one of two major pathways ( lymphoid or myeloid).   Stem cells then become progenitor cells for each type of mature blood cell. These cells have lost the capacity for self-renewal and are committed to a given cell lineage. T&B progenitors, and progenitor cells for erythrocytes, neutrophils, eosinophils, basophils, monocytes, mast cells, and platelets.

Pluripotent Stem Cell gives rise to:
 

Myeloid Stem Cell	progenitor cells for each cell type		neutrophil
			monocyte macrophage
			eosinophil
			erythrocyte
			megakaryocytes
			mast cells
			basophils

Or, Pluripotent Stem Cell gives rise to:

Lymphoid Stem Cell	progenitor B	precursor B	mature B lymphocyte	Plasma Cell
				Memory B Cell
	or
	progenitor T	precursor Tc	mature Tc	CTL
				memory Tc
		or
		precursor Th	mature Th	Th1
				Th2
Null Cells?????

B cell development to the stage of the mature B lymphocyte is completed within the bone marrow. Further differentiation into Plasma Cells or memory B cells does not occur until the mature (but naïve) B lymphocyte encounters specific antigen. T cell development to the stage of the precursor T lymphocyte occurs within the bone marrow. The precursor T lymphocytes (otherwise known as pre-Ts) then must go to the thymus to complete maturation. When mature T lymphocytes leave the thymus, they leave as mature (but naïve ) Tc (T cytotoxic lymphocytes) or Th (T helper lymphocytes). Further differentiation does not occur until the mature T cells encounter antigen (presented to the T cell in association with MHC proteins).

Progenitor committment depends upon the acquisition of responsiveness to certain growth factors. The particular microenvironment within which the progenitor cell resides controls differentiation. The hematopoietic cells grow and mature on a meshwork of stromal cells, which are nonhematopoietic cells that support the growth and differentiation of the hematopoietic cells. Include: fat cells, endothelial cells, fibroblasts, and macrophages.

These cells provide a HEMATOPOIETIC -INDUCING MICROENVIRONMENT

This microenvironment consists of the actual cellular matrix and either membrane-bound or diffusable growth factors.

Hematopoietic Growth Factors

Colony Stimulating Factors
multilineage colony-stimulating factor (multi-CSF or IL-3)
granulocyte-macrophage colony stimulating factor (GM-CSF)
macrophage colony stimulating factor (M-CSF)
granulocyte colony-stimulating factor (G-CSF)
Erythropoietin - Induces terminal erythrocyte development and regulates RBC production.

IL-4
IL-5
IL-6
IL-7
IL-8
IL-9

These growth factors are present at extremely low concentrations and biological activity at concentrations as low as 10^-12 M.
Now all of the genes have been cloned and recombinant products have definable activity in culture.

CSFs- act in a stepwise manner inducing proper maturation. IL-3 [multi-CSF] acts early, possibly even at the level of the pluripotent stem cell, to induce formation of the nonlymphoid cells (erythrocytes, monocytes, granulocytes[neutrophils, eosinophils, basophils], and megakaryocytes).

GM-CSF acts at a slightly later stage, but it also induces formation of all the nonlymphoid blood cells. M-CSF and G-CSF act still later to promote the formation of monocytes and granulocytic cells, respectively.

IL-4 - stimulates B progenitors, mast progenitors, and basophil progenitors
IL-5 - stimulates eosinophil progenitor
IL-6 - stimulates the myeloid stem cell
*IL-7 - induces the differentiation of lymphoid progenitor into B progenitor and T progenitor
IL-8 - stimulates the neutrophil progenitor
IL-9 - stimulates mast cell growth

Committment of a progenitor cell is associated with the expression on the cell membrane of membrane receptors that are specific for particular cytokines.

Hematopoiesis is a continuous process throughout adulthood. Production of mature blood cells equals their loss. Estimated that the average human must produce 3.7X10¹¹ blood cells per day.

This process is regulated by complex mechanisms.

Cell division and differentiation during hematopoiesis are balanced by apoptosis - there must by maintenance of a steady state.

During apoptosis you see:

• a decrease in cell volume
• modification of the cytoskeleton with pronounced membrane blebbing
• condensation of chromatin
• degradation of DNA into oligonulceosomal fragments
• shedding of apoptotic bodies
• quick phagocytosis to prevent inflammation

If apoptosis fails, a leukemic state can occur.

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