IntroductionConventionally, human hematopoietic stem cells (HSCs) have been purified on the basis of the expression of cell surface molecules such as CD34 and CD133. [1][2][3][4][5] Cells expressing CD34 are capable of long-term hematopoietic reconstitution in immune-deficient mice and fetal sheep, [1][2][3]6,7 and most clinical protocols involving gene transfer, purified stem cell transplantation, and stem cell expansion have been designed with the use of CD34 ϩ populations. [8][9][10] However, findings in a variety of mammalian systems suggest that the human hematopoietic stem cell compartment is heterogeneous, including an array of cell phenotypes that exhibit repopulating function. [11][12][13][14] In fact, human CD34 ϩ and CD34 Ϫ populations possess repopulating ability, and CD34 expression is reversible in mouse and human cells. [15][16][17][18][19] Although CD34 selection has proven extremely useful for the isolation and characterization of human cells with enhanced repopulating function, there are several limitations to purifying hematopoietic cells based solely on cell surface phenotype. First, cell surface markers can vary between species and stem cell source. Murine long-term repopulating cells have been purified to a single cell with the use of CD34 Ϫ , c-kit ϩ , Sca-1 ϩ , Lin Ϫ cell markers, 11 whereas identification of a human single cell phenotype capable of repopulating murine or fetal sheep xenograft models remains elusive. 1,12,14 Second, human stem cell phenotype can be altered by cell cycle progression, 20,21 ex vivo culture, 14,19,22 and transplantation in vivo, 12,15,16 indicating a dissociation between hematopoietic cell phenotype and repopulating cell function. Third, the phenotype of transplanted stem cells may remain constant despite reduced functional activity. Cytokinemobilized peripheral blood cells demonstrate increased CD34 expression without an increase in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) repopulating ability. 23,24 Finally, purification of human stem cells on the basis of hematopoietic markers may select cells with restricted developmental potential and may exclude cells with alternate stem cell or progenitor functions. Thus, methods to efficiently isolate human stem cells without relying entirely on phenotypic cell surface molecules are desirable.One promising strategy is HSC isolation according to a conserved stem cell function rather than phenotype. In the murine system, lymphohematopoietic stem cells have been isolated according to the high expression of the detoxifying enzyme aldehyde dehydrogenase (ALDH). [25][26][27] Cytosolic ALDH is also expressed at high levels in human hematopoietic progenitors, 28 (4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-5-proprionic acid) fluorochrome that is metabolized by ALDH to an aminoacetate anion, retained within the cell because of its negative charge. Thus, the amount of fluorescent product that accumulates in viable cells correlates to ALDH activity, and cells with high ALDH activity can be selected from...
Transplanted adult progenitor cells distribute to peripheral organs and can promote endogenous cellular repair in damaged tissues. However, development of cell-based regenerative therapies has been hindered by the lack of preclinical models to efficiently assess multiple organ distribution and difficulty defining human cells with regenerative function. STEM CELLS 2008; 26:611-620 Disclosure of potential conflicts of interest is found at the end of this article.
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