Reversible expression of CD34 by adult human bone marrow long-term engrafting hematopoietic stem cells

Zanjani, Esmail D.; Almeida-Porada, Graça; Livingston, Anne G.; Zeng, Haiqun; Ogawa, Makio

doi:10.1016/s0301-472x(03)00051-1

Cited by 78 publications

(67 citation statements)

References 34 publications

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“…1 CD34 Ϫ cells represent a kinetically and functionally resting stem cell subset that needs to be activated to generate a CD34 ϩ cell population with high proliferative and engraftment potential. 2,3 Acquisition of CD34 expression on human HSCs is associated with in vitro hematopoietic activity and cell-cycle recruitment. 4 CD34 Ϫ /CD34 ϩ transition results in metabolic activation and down-regulation of growth-inhibitory pathways, and CD34 ϩ stem cells show a significant up-regulation of self-renewal-, commitment-, and engraftment-related genes.…”

Section: Introductionmentioning

confidence: 99%

Molecular and functional analysis of the stem cell compartment of chronic myelogenous leukemia reveals the presence of a CD34− cell population with intrinsic resistance to imatinib

Lemoli

Salvestrini

Bianchi

et al. 2009

Blood

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IntroductionSeveral studies have demonstrated that normal hematopoietic stem cells (HSCs) exist in 2 functional states that can be distinguished based on CD34 expression. 1 CD34 Ϫ cells represent a kinetically and functionally resting stem cell subset that needs to be activated to generate a CD34 ϩ cell population with high proliferative and engraftment potential. 2,3 Acquisition of CD34 expression on human HSCs is associated with in vitro hematopoietic activity and cell-cycle recruitment. 4 CD34 Ϫ /CD34 ϩ transition results in metabolic activation and down-regulation of growth-inhibitory pathways, and CD34 ϩ stem cells show a significant up-regulation of self-renewal-, commitment-, and engraftment-related genes. 5 No data are presently available on the existence of a stem cell population devoid of CD34 expression in leukemic hematopoiesis.Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder of HSCs that have acquired a BCR-ABL fusion gene. The encoded 210-kDa protein has constitutively elevated tyrosine kinase activity that results in a large variety of biochemical changes in leukemic stem cells (LSCs) mainly inducing growth factor-independent proliferation, inhibition of apoptosis, and alteration of adhesive properties. 6 There is an increasing body of evidence indicating that, similar to normal hematopoiesis, a kinetically quiescent stem cell population can be isolated within the CD34 ϩ LSC compartment. 7 These G 0 CML cells are able to repopulate immunodeficient mice 8 and show a different transcriptional profile from dividing CD34 ϩ cells. 9 More importantly, the dissection of the stem cell pool in CML has allowed the characterization of subsets of CD34 ϩ LSCs resistant, in vitro and in vivo, to targeted therapies with BCR-ABL inhibitors. [10][11][12] Multiple mechanisms of drug resistance have been described, including kinetic quiescence per se, 10 increased expression level of BCR-ABL, and altered expression of ABCB1, ABCG2, and OCT1 cell membrane drug transporter genes in the most primitive CD34 ϩ /CD38 Ϫ LSCs. 13 Taken together, these findings stress the importance of gaining further understanding of the molecular and functional properties of the stem cell compartment in CML, in view of the development of more effective therapies.To this end, in the present study, we assessed the gene expression profile and the functional characteristics of a novel Lin Ϫ CD34 Ϫ stem cell population in CML patients at diagnosis. Our data demonstrate that approximately one-third of Lin Ϫ CD34 Ϫ cells are leukemic and capable of engraftment in immunodeficient mice. Overall, molecular analysis showed 1827 transcripts differentially expressed in CML HSC subpopulations compared with normal counterparts, genes affecting many cellular functions associated with the neoplastic phenotype. Microarray data also highlighted the highest transcriptome differences between CML Lin Ϫ CD34 Ϫ cells and their normal counterparts. Functional The online version of this article contains a data supplement.The publication co...

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Section: Introductionmentioning

confidence: 99%

Molecular and functional analysis of the stem cell compartment of chronic myelogenous leukemia reveals the presence of a CD34− cell population with intrinsic resistance to imatinib

Lemoli

Salvestrini

Bianchi

et al. 2009

Blood

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“…Conversely, the human BM-derived CD34 À cell population generates CD34 þ -repopulating cells in vivo, thus indicating that the expression of CD34 antigen can be reversible on human BM-derived HSCs. 27,28 As we reported earlier, 7 human CB-derived CD34 À SRCs generate CD34 þ SRCs in vitro as well as in vivo. In contrast to BM-derived HSCs, 27,28 human CB-derived CD34 þ SRCs do not convert to CD34 À SRCs for at least 16 weeks after transplantation.…”

Section: Discussionmentioning

confidence: 62%

“…27,28 As we reported earlier, 7 human CB-derived CD34 À SRCs generate CD34 þ SRCs in vitro as well as in vivo. In contrast to BM-derived HSCs, 27,28 human CB-derived CD34 þ SRCs do not convert to CD34 À SRCs for at least 16 weeks after transplantation. 7 However, it remains to be determined whether human CB-derived CD34 þ SRCs can convert to CD34 À SRCs.…”

Section: Discussionmentioning

confidence: 62%

“…26 On the other hand, human BM-derived CD34 þ HSCs have been reported to convert to CD34 À HSCs in vivo. 27,28 Both these studies showed that the conversion of the CD34 expression occurs at least 8-15 months after the transplantation of purified Lin À CD34 þ or Lin À CD34 þ CD38 À cells in either preimmune fetal sheep or homozygous bg.bg/nu.nu/xid.xid (bnx) mice. These studies indicate the possibility that the human BM-derived CD34 þ cell population can act as a reservoir for the generation of CD34 À cells.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, much longer observation periods (41 year) will thus be needed, as suggested in earlier reports. 27,28 Interestingly, human BM-derived Lin À CD34 À cells did not show any SRC activity when they were directly transplanted into NOD/SCID mice by IBMI (Sonoda et al unpublished data). These data are consistent with the findings of a recent report, 29 which describes that mouse BM stromal cell line, HESS-5, engineered to produce angiopoietin-1, supports the induction of hematopoietic activity in human BM-derived CD34 À cells, thus suggesting that the characteristics of CD34 À LT-HSC found in human CB and BM are different classes of primitive HSC.…”

Section: Discussionmentioning

confidence: 99%

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In vivo dynamics of human cord blood-derived CD34− SCID-repopulating cells using intra-bone marrow injection

et al. 2009

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The identification of human CD34-negative (CD34 À ) hematopoietic stem cells (HSCs) provides a new concept for the hierarchy in the human HSC compartment. This study investigated the long-term repopulating capacity and redistribution kinetics of human cord blood-derived CD34 À severe combined immunodeficiency (SCID)-repopulating cells (SRCs) and compared them with those of CD34 þ CD38 þ and CD34 þ CD38 À SRCs using the intra-bone marrow injection (IBMI) to clarify the characteristics of CD34 À SRCs. On the basis of the limiting dilution analyses data, estimated numbers of CD34 þ CD38 þ , CD34 þ CD38 À , and CD34 À SRCs were transplanted to NOD/SCID mice by IBMI. The human cell repopulation at the site of injection and the other bones were serially investigated. Interestingly, CD34 þ CD38 þ , CD34 þ CD38 À , and CD34 À SRCs began to migrate to other bones 2 and 5 weeks after the transplantation, respectively. Accordingly, the initiation of migration seemed to differ between the CD34 þ and CD34 À SRCs. In addition, CD34 þ CD38 þ SRCs only sustained a shortterm repopulation. However, both CD34 þ CD38 À and CD34 À SRCs had longer-term repopulation capacity. Taken together, these findings showed that CD34 À SRCs show different in vivo kinetics, thus suggesting that the identified CD34 À SRCs are a distinct class of primitive HSCs in comparison to the CD34 þ CD38 þ and CD34 þ CD38 À SRCs.

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Hematopoietic stem cells

Bonnet

2003

Birth Defects Research Pt C

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Considerable effort has been made in recent years in defining the embryonic origin of the hematopoietic stem cell (HSC). Using transgenic mouse models, a number of genes that regulate the formation, self-renewal, or differentiation of HSCs have been identified. Of particular interest, it has recently been shown that key regulators of definitive blood formation played a crucial role in adult HSC development. Specifically, the use of some of these regulatory molecules has dramatically improved the potential of adult HSC expansion. Furthermore, the elucidation of the molecular phenotype of the HSC has just begun. Finally, unexpected degrees of HSC developmental or differentiation plasticity have emerged. In this review, we will summarize the recent advances made in the human HSC field, and we will examine the impacts these discoveries may have clinically and on our understanding of the organization of the human hematopoietic system.

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Reversible expression of CD34 by adult human bone marrow long-term engrafting hematopoietic stem cells

Cited by 78 publications

References 34 publications

Molecular and functional analysis of the stem cell compartment of chronic myelogenous leukemia reveals the presence of a CD34− cell population with intrinsic resistance to imatinib

Molecular and functional analysis of the stem cell compartment of chronic myelogenous leukemia reveals the presence of a CD34− cell population with intrinsic resistance to imatinib

In vivo dynamics of human cord blood-derived CD34− SCID-repopulating cells using intra-bone marrow injection

Hematopoietic stem cells

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