Complexity of the human hematopoietic stem cell compartment

We recently demonstrate a phenotypic heterogeneity of Scid Repopulating Cells (SRCs) within the Lin-CD34+CD38- population. Some CD34+-SRC expressed myeloid markers like CD33, CD13, CD123 while others are devoid of these markers. The presence of myeloid markers on HSCs is consistent with the lineage-priming hypothesis described previously in the mouse system. The heterogeneity in human HSC phenotype is consistent with the heterogeneity observed within SRCs using viral tracking studies. Some repopulating cells do not contribute to haematopoiesis until later time points while others appear to be relatively short lived. The other level of complexity of the HSC compartment comes from the expression or not of CD34 antigen. The relationship between the two types of SRCs (CD34- and CD34+; Lin-CD34+CD38-) in vivo is still largely unknown. In the mouse system, it has been shown that murine CD34– stem cells can be induced to express CD34, and to increase engraftment capacity, following in vivo exposure to 5-fluorouracil (5FU) or in vitro exposure to cytokines. Whether this modulation corresponds to cell activation or induction of cell cycling is unclear. However, to date, it is still unknown whether the human system is organised in the same way. We will summarise some new data from our group showing that CD34-_ SRC are more primitive that CD34+_ SRC fraction using serial transplantation experiments. We also went on to characterise the adhesion machinery repertoire, cell-cycle status and expression of different downstream/upstream genes reported to be important in the maintenance of hHSC self-renewal process (e.g., Notch, Wnt, Sonic Hedgehog pathways) with the aim to find the reason for the different potential/kinetics of engraftment of these two types of SRCs. Overall, our data indicate that Lin-CD34-CD38- is the most primitive stem cell pool in the hHSC hierarchical organisation, which might have some clinical implications for transplantation, and expansion procedures.