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hematopoietic stem cells

Hematopoietic stem cells make up the so-called primitive stem cell compartment. These cells are very primitive pluripotent cells with an extensive capacity for self-maintenance and self-renewal persisting throughout adult life. The term Self-renewal potential refers to the fact that these cells can proliferate without differentiation, giving rise to progeny identical in appearance and differentiation potential. The differentiation potential of these cells is unlimited, i.e., these cells can give rise to any of the cell types found in the blood.

Hematopoietic stem cells can be isolated from various sources, including the bone marrow, umbilical cord blood (UCBSC; umbilical cord blood stem cells), fetal liver, and mobilized peripheral blood (PBSC, peripheral blood stem cells). The compartment of hematopoietic stem cells appears to be heterogeneous since the various types of stem cells may differ in their immunogenic and reconstitutive capacity (Korbling and Anderlini, 2001). They also appear to differ in their sensitivity towards various growth factors although these differences cannot be explained by differences in the expression levels of corresponding receptors (De Waele et al, 2004). Hematopoietic stem cells from different sources also exhibit striking variations in homing efficiency to the bone marrow, which may influence the rate of hematopoietic reconstitution following transplantation (Szilvassy et al, 2001). Signal transduction mechanisms and cell-fate choices in hematopoietic stem cells in vivo and in vitro are very complex (Zhang and Lodish, 2008).

Totipotent stem cells differentiate first into myeloid stem cells and lymphoid stem cells. These two cell types are called multipotential stem cells. They are also capable of extended self-renewal and have the capacity of extended differentiation but their differentiation potential is already restricted. Lymphoid stem cells give rise to all categories of mature lymphocytes. CMLP cells [common myelolymphoid progenitors] have been identified in murine fetal liver and constitute common myelolymphoid progenitor cells that give rise to myeloid cells, T-cells, and B-cells but not erythroid cells.

Myeloid stem cells give rise to erythrocytes, granulocytes, monocytes, and platelets. Dysfunctions of lymphoid stem cell can give rise to so-called lymphoproliferative malignancies such as acute lymphocytic leukemia. Dysfunctions in myeloid stem cells can give rise to so-called myeloproliferative malignancies such as acute myeloid leukemia.

Multipotential stem cells develop into a variety of so-called progenitor cells, which have only a limited capacity of self-renewal and have a more reduced differentiation capacity (see, for example: CFU, CFC, BFU-E, CFU-E, CFU-Eo, CFU-G, CFU-GEMM, CFU-GM, CFU-M, CFU-MEG). Progenitor cells give rise to precursor cells, the differentiation of which is even more restricted to individual lineages. Dysfunctions of stem cells can lead to aplastic anemia or certain types of leukemia.

Hematopoietic stem cells are the only cells capable of colonizing lethally irradiated bone marrow to reconstitute the entire hematopoietic system. This activity is referred to as MRA (marrow repopulating ability) and has been used also to develop a competitive repopulation assay as one of the assays allowing detection of stem cells.

The hematopoietic stem cell pool consists of long-lived quiescent cells (see also: Cell cycle). Entrance of stem cells into the cell cycle is usually induced only in the presence of a variety of different known and unknown or biochemically uncharacterized cytokines. This is probably a safeguard mechanism preventing an exhaustion of the stem cell compartment through excess differentiation induced by individual late-acting differentiation inducing cytokines, which may be present, for example, under conditions of chronic infections.

Hematopoietic stem cells are quite rare and constitute approximately 4-400/10**5 normal bone marrow cells, depending upon the assay used. Hematopoietic stem cells also circulate in the peripheral blood. A third source of these cells is umbilical cord blood, which is extremely enriched in these cells.

Quantitative analyses of these primitive hematopoietic cell populations are important both for basic biology and for clinical applications. long-term BMC (bone marrow culture) and growth in semi-solid media (see also: Colony formation assay) have been used to develop assay systems for the purification, characterization, or detection of pluripotent stem cells, early progenitor cells, or precursor cells (for an analysis technique see also: Limiting dilution analysis).

Assays for clones or colonies arising from a single stem cell are called Clonogenic assays. Unfortunately, many conventional assays fail to measure the most important characteristics of primitive hematopoietic stem cells: long-term bone marrow repopulating ability and maximal differentiating ability.

Early hematopoietic stem cells have been defined in vitro as Blast colony-forming cells, CAFC (cobblestone area-forming cells), CFU-A; CFC-Mix, LTC-IC (long-term culture-initiating cells), LTRC (long-term repopulating cells), and HPP-CFC (high proliferative potential colony-forming cells). In mice they have been described as KTLS cells or LSK cells or KSL cells. ML-IC [Myeloid-Lymphoid initiating cells] closely resemble hematopoietic stem cells, and YS-HSC [yolk sac hematopoietic stem cells] have been shown to have greater reproductive capability than hematopoietic stem cells obtained from fetal liver, umbilical cord blood, or adult bone marrow. CD45(+) liver side population tip cells are tissue-specific stem cells obtained from murine liver
In vivo, stem cells have been defined as CFU-S (colony-forming unit spleen) and CRU (competitive repopulating unit); see: MRA, marrow repopulating ability). Enumeration of CRUs is now believed to yield one of the closest estimates of the number of true hematopoietic stem cells. Transplantation of hematopoietic stem cells into SCID mice or NOD/SCID mice and reconstitution of hematopoiesis has been used to define stem cells as SRC (SCID repopulating cells).

The compartment of hematopoietic stem cells is now believed to contain a continuum of cell types in various stages of differentiation. Some of these cells are unlikely to be readily detectable with currently available in vitro clonogenic assays. Indeed, the individual cell types detected in stem cell assays are not identical and show differences with regard to support hematopoiesis, the length of time over which they function, and the differentiative potential (Ratajczak, 2008).

Primitive cell types can be detected by various strategies, including Colony formation assay, Delta assay, Limiting dilution analysis, long-term BMC (bone marrow culture), or by their ability to fully reconstitute hematopoiesis in vivo (see: MRA, marrow repopulating ability).

Primitive cell types can be enriched selectively and studied further by treatment with compounds such as Fluorouracil or 4-HC (4-hydroperoxycyclophosphamide), the latter compound being particularly useful for tumor cell purging. The cells can be enriched also by Ficoll gradient centrifugation of total bone marrow and enrich them from mature blood cells by removing mature cells that carry specific lineage markers. It is possible also to isolate them by differential fluorescence-activated cell sorter (FACS) selection. The most frequently employed dyes are Hoechst 33342 or rhodamine-123 (see: CFU-S, LTRC, side population cells).

These cells cannot be identified morphologically, but resemble lymphocytes. Early hematopoietic stem cells are among those expressing the cell surface glycoprotein CD34 or murine Sca-1 and can be identified also, therefore, by using appropriate monoclonal antibodies. The vast majority of these stem cells have receptors for SCF (stem cell growth factor), which promotes their proliferation. In order to enrich cell sources for putative hematopoietic stem cells, a selection is made for so-called lineage negative cells, which excludes the more differentiated cell types.

The molecular nature of the mechanisms underlying stem cell renewal and of mechanisms preventing exhaustion of stem cell pools throughout the entire life span of an organism are still under intensive study but are as yet largely unknown. These processes critically depend on the maintenance of a functional hematopoietic microenvironment (see: hematopoiesis) providing membrane-bound components and soluble factors. The plethora of cytokines governing these processes are known as collectively hematopoietins (hematopoietic growth factors). Nie et al (2008) have reported that CXCL12 produced by bone marrow stromal cells is not only the major chemoattractant for hematopoietic stem cells but also a regulatory factor that controls the quiescence of primitive hematopoietic cells. CXCL12 inhibits entry of primitive hematopoietic cells into the cell cycle, and inactivation of its receptor, CXCR4, in hematopoietic stem cells causes excessive hematopoietic stem cells proliferation. The hyperproliferative hematopoietic stem cells are able to maintain a stable stem cell compartment and sustain hematopoiesis.

Recent progress has been made in defining the molecular basis of commitment and differentiation of hematopoietic cells at the genetic level with the identification of Homeotic genes that appear to be of fundamental importance in these processes. And it is to be expected that a close examination of transgenic mice overexpressing or lacking expression of specific cytokines (see also: Knock-out) will further contribute to the elucidation of mechanisms underlying stem cell physiology.

For other relevant entries see also: Cell types. For other entries pertaining to hematopoiesis see also the Hematology Dictionary section of this encyclopedia.

LAST MODIFIED: January 2002

See REFERENCES for entry hematopoietic stem cells

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