Chapter 068. Hematopoietic Stem Cells (Part 2)

Developmental Biology of Hematopoietic Stem CellsDuring development, blood cells are produced at different sites. Initially, the yolk sac provides oxygen-carrying red blood cells, and then several sites of intraembryonic blood cell production become involved. These intraembryonic sites engage in sequential order, moving from the genital ridge at a site where the aorta, gonadal tissue, and mesonephros are emerging to the fetal liver and then, in the second trimester, to the bone marrow and spleen. As the location of stem cells changes, the relative abundance of cells they produce also changes, progressively increasing in the complexity of cell types from...
Nội dung trích xuất từ tài liệu:
Chapter 068. Hematopoietic Stem Cells (Part 2) Chapter 068. Hematopoietic Stem Cells (Part 2) Developmental Biology of Hematopoietic Stem Cells During development, blood cells are produced at different sites. Initially,the yolk sac provides oxygen-carrying red blood cells, and then several sites ofintraembryonic blood cell production become involved. These intraembryonicsites engage in sequential order, moving from the genital ridge at a site where theaorta, gonadal tissue, and mesonephros are emerging to the fetal liver and then, inthe second trimester, to the bone marrow and spleen. As the location of stem cellschanges, the relative abundance of cells they produce also changes, progressivelyincreasing in the complexity of cell types from those simply carrying oxygen toplatelets supporting a more complex vasculature to the cells of innate immunityand finally to the cells of adaptive immunity. Stem cell proliferation remains high,even in the bone marrow, until shortly after birth, when it appears to dramaticallydecline. The cells in the bone marrow are thought to arrive by the bloodbornetransit of cells from the fetal liver after calcification of the long bones has begun.The presence of stem cells in the circulation is not unique to a time window indevelopment. Rather, hematopoietic stem cells appear to circulate throughout life.The time that cells spend freely circulating appears to be brief (measured inminutes in the mouse), but the cells that do circulate are functional and can beused for transplantation. The number of stem cells that circulate can be increasedin a number of ways to facilitate harvest and transfer to the same or a differenthost. Mobility of Hematopoietic Stem Cells Cells entering and exiting the bone marrow do so through a series ofmolecular interactions. Circulating stem cells (through CD162 and CD44) engagethe lectins P- and E-selectin on the endothelial surface to slow the movement ofthe cells to a rolling phenotype. Stem cell integrins are then activated andaccomplish firm adhesion between the stem cell and vessel wall, with aparticularly important role for stem cell VCAM-1 engaging endothelial VLA-4.The chemokine CXCL12 (SDF1) interacting with stem cell CXCR4 receptors alsoappears to be important in the process of stem cells getting from the circulation towhere they engraft in the bone marrow. This is particularly true in thedevelopmental move from fetal liver to bone marrow; however, the role for thismolecule in adults appears to be more related to retention of stem cells in the bonemarrow rather the process of getting them there. Interrupting that retention processthrough either specific molecular blockers of the CXCR4/CXCL12 interaction,cleavage of CXCL12, or downregulation of the receptor can all result in therelease of stem cells into the circulation. This process is an increasingly importantaspect of recovering stem cells for therapeutic use as it has permitted theharvesting process to be done by leukapheresis rather than bone marrow puncturesin the operating room. Refining our knowledge of how stem cells get into and outof the bone marrow may improve our ability to obtain stem cells and make themmore efficient at finding their way to the specific sites for blood cell production,the so-called stem cell niche. Hematopoietic Stem Cell Microenvironment The concept of a specialized microenvironment, or stem cell niche, wasfirst proposed to explain why cells derived from the bone marrow of one animalcould be used in transplantation and again be found in the bone marrow of therecipient. This niche is more than just a housing site for stem cells, however. It isan anatomic location where regulatory signals are provided that allow the stemcells to thrive, to expand if needed, and to provide varying amounts of descendantdaughter cells. In addition, unregulated growth of stem cells may be problematicbased on their undifferentiated state and self-renewal capacity. Thus, the nichemust also regulate the number of stem cells produced. In this manner, the nichehas the dual functions of serving as a site of nurture but imposing limits for stemcells: in effect, acting as both a nest and a cage. The niche for blood stem cells changes with each of the sites of bloodproduction during development, but for most of human life it is located in the bonemarrow. Within the bone marrow, at least two niche sites have been proposed: ontrabecular bone surfaces and in the perivascular space. Stem cells may be found inboth places by histologic analysis, and functional regulation has been shown at thebone surface. Specifically, bone-forming mesenchymal cells, osteoblasts,participate in hematopoietic stem cell function, affecting their location,pro ...