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External signals that control cell fate collectively make up the stem cell niche.

Secreted factors from other cell types support survival of distinct progenitor populations. Integrins and extracellular matrices also affect cell fate. Integrins hold cells in the right place from tissue. In absence of integrin expression, the stem cell departs from its niche through differentiation or apoptosis. Integrins are also signaling receptors and can directly activate growth factor receptors. Extracellular matrix (ECM) proteins help modulate expression and activation of integrins and concentration of secreted factors in the niche. (70)

	HEMATOPOIETIC REGULATORY PATHWAYS
What Controls Differentiation of Hematopoietic Stem Cells? Because of the required balance between self-renewal and differentiation, mechanisms that govern stem cell fate decisions must be under tight yet flexible control. Hematopoietic stem cell differentiation is controlled by the combined interactions of signal molecules and positive and negative transcription factors. However little is concretely known about the molecular nature of these mechanisms.
INTRINSIC CONTROLS
Intrinisc stem cell regulation involves: The proteins responsible for setting up asymmetric cell divisions Nuclear factors controlling gene expression and chromosomal modifications Clocks that effect the number of rounds of division These include transcription factors and cell cycle proteins that promote or inhibit changes in the cell cycle. SCL/Tal-1 is an example of a known transcription factor that is essential to blood cell formation, especially T lymphocytes. Cyclin-dependent kinase inhibitor p21cip1/waf1 is an example of a clock protein and plays a critical role in inhibiting differentiation and preventing stem cell exhaustion. Hox genes also play an important role in the regulation of proliferation. Evidence suggests involvement of Hox genes in the pathogenesis of human leukemias. (70)
EXTERNAL CONTROLS
External signals that control cell fate collectively make up the stem cell niche. Secreted factors from other cell types support survival of distinct progenitor populations. Integrins and extracellular matrices also affect cell fate. Integrins hold cells in the right place from tissue. In absence of integrin expression, the stem cell departs from its niche through differentiation or apoptosis. Integrins are also signaling receptors and can directly activate growth factor receptors. Extracellular matrix (ECM) proteins help modulate expression and activation of integrins and concentration of secreted factors in the niche. (70)
GENE EXPRESSION OF HSC CELLS
Recently a genome-wide expression analysis of murine fetal liver stem cells was performed to help define regulatory pathways of the hematopoietic stem cell. Analysis of the entire sequence has revealed at least 161 transcription factors, 174 cell-surface or membrane associated molecules, 28 secreted proteins, and 147 signaling molecules (see full list here). Full-length sequences for five of these molecules that possessed characteristics suggestive of regulatory roles were obtained. Expression differences among closely related progenitor cells suggest a high degree of precision in transcriptional control mechanisms. (72) (72) Alignments of important motifs (right) and subcellular localization (above) for five proteins identified in hematopoietic stem cells
WHY IS IT IMPORTANT TO UNDERSTAND SIGNALING FACTORS THAT CAUSE DIFFERENTIATION IN VITRO?
In Vitro differentiation of ES cells provides an opportunity to better understand human hematopoiesis and could lead to a source of cells for transfusion and transplantation therapies. In vitro hematopoietic differentiation has therapeutic implications, such as the derivation of erythrocytes and platelets for transfusions and hematopoietic stem cell transplantation. Blood products could potentially be created in virtually unlimited amounts. They could even be genetically engineered to combat specific diseases or treatment of hematologic malignancies. In order to access the medical possibilities of these stem cells we must first we must understand the controls that cause them to differentiate. (65)