SCL Expression at Critical Points in Human Hematopoietic Lineage Commitment - 《stemcells》2004-2005文献干细胞之家



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发表于 2009-3-5 10:50 |只看该作者 |倒序浏览 |打印

a Childrens Hospital Los Angeles, Los Angeles, California, USA;4 v" B1 u- }, A; v4 M* Z4 ^2 u
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b Barrow Neurological Institute, Phoenix, Arizona, USA

Key Words. Transcription factors ? Hematopoietic progenitors ? Erythropoiesis ? Leukemia7 l0 k) S9 A/ f1 ~6 h

Correspondence: Gay M. Crooks, M.D., Childrens Hospital Los Angeles, M.S.#62, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA. Telephone: 323-669-5690; Fax: 323-660-1904; e-mail: gcrooks@chla.usc.edu
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ABSTRACT
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The stem cell leukemia (SCL or tal-1) gene was initially identified as a translocation partner in a leukemia that possessed both lymphoid and myeloid differentiation potential . In subsequent studies, aberrant expression of SCL, arising from translocations and from site-specific recombinase-mediated deletions in the SCL gene, was associated with T-cell acute lymphocytic leukemia (T-ALL) .
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The SCL gene encodes a basic helix-loop-helix transcription factor  that heterodimerizes with the E2A gene products  and interacts with a subunit of the basal transcription factor TFIIH . In addition to the E2A gene products, SCL has been shown to interact with GATA-1, LM0 (LIM-only proteins), Lbd1, Sp-1, and others to form larger protein complexes  that can either repress or enhance expression of target genes.  s, _7 n0 G/ R  f+ F, T

Murine models that examined hematopoiesis in the absence of SCL expression suggested that SCL was important in hematopoietic stem cell (HSC) function. Initial studies of SCL knockout mice showed a failure in primitive yolk sac hematopoiesis that resulted in embryonic lethality . Similarly, studies of chimeric animals generated by the injection of SCL–/– embryonic stem (ES) cells into normal blastocysts showed that definitive adult hematopoiesis could only arise from cells that expressed SCL . The recent development of mouse models in which SCL expression can be modulated has aided in precisely identifying the murine hematopoietic activities dependent on the expression of SCL. Studies of SCL-conditional mutants showed that the production but not self-renewal or engraftment of long-term repopulating HSCs (LT-HSCs) is dependent on SCL . These mice also showed that SCL is required for the production of erythrocytes and megakaryocytes but not for lymphoid or myeloid differentiation . However, the abrogation of SCL resulted in reduced short-term repopulating HSC (ST-HSC) function  and skewed multilineage repopulation . Studies of murine hematopoietic repopulation from HSCs in which levels of SCL were manipulated via expression of a dominant-negative form of SCL or by overexpression of wild-type SCL provided evidence that SCL may play a role in myeloid versus lymphoid differentiation .' T2 G* i. A3 G5 O  v2 L% w

Studies of human cell lines in which expression of either SCL or SCL antisense was enforced suggest that SCL may play several roles in human hematopoiesis. These roles include providing protection from apoptosis, enhancing cell-cycle progression and long-term culture-initiating cell (LTC-IC) activity, inhibiting myeloid differentiation, and promoting erythroid differentiation . Evidence from the few studies of SCL function in primary human hematopoietic cells involved in vitro differentiation assays and suggests that at least some of these are legitimate roles for SCL in normal human hematopoiesis. Enforced SCL expression in primary human progenitors increases erythroid and megakaryocyte colony formation, selectively increases the size of erythroid colonies, and, in some cases, reduces granulocyte colony formation . Conversely, when SCL expression is decreased by treating primary human progenitors with SCL antisense, erythroid colony formation is significantly decreased, although no effect on the formation of granulocyte colonies is observed . Little is known of SCL expression during normal human hematopoietic differentiation.

Given that SCL was originally identified in a leukemia with both lymphoid and myeloid differentiation potential  and that murine studies suggest a role for SCL in lymphoid and myeloid lineage commitment , we were interested in whether SCL might play some role in early stages of normal human lymphoid and myeloid differentiation. The classic model of hematopoiesis proposes that pluripotent HSCs in umbilical cord blood (CB) (CD34  CD38–CD7–) and bone marrow (BM) (CD34  CD38–) give rise to progenitors that have committed to either a lymphoid cell fate (common lymphoid progenitor ) or myeloid/erythroid cell fate (common myeloid progenitor ). CLPs are believed to ultimately give rise to single-lineage progenitors committed to becoming T, B, or natural killer (NK) cells. CMPs are postulated to generate two populations of bipotential progenitors, the granulocyte/monocyte progenitor (GMP) and the megakaryocyte/erythroid progenitor (MEP).) @! F! E/ K# ^8 e
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Recent studies have identified, based on surface immunophenotype, several of the lymphoid, myeloid, and erythroid differentiation intermediates predicted by the classic model of hematopoietic differentiation. Fluorescence-activated cell sorting (FACS) of Lin–CD34 CD38  CB and BM progenitors based on coexpression of CD45RA and the interleukin-3 receptor alpha (IL-3R) allows the isolation of functional CMP (IL-3R CD45RA–), GMP (IL-3R CD45RA ), and MEP (IL-3R–CD45RA–) populations. The population with CLP function within human BM has been defined as Lin–CD34 CD10 . More recently, studies in our laboratory have shown that the human CB population that functions as a CLP is CD34 CD38–CD7  .

Determining SCL expression at precise points in normal hematopoietic differentiation is key to clarifying the roles of SCL in this process and may provide clues to the mechanisms through which the SCL gene product acts. SCL expression has not been examined in precisely defined populations of lymphoid, myeloid, or erythroid progenitors isolated from primary human hematopoietic sources. Our studies follow SCL expression from the pluripotent HSCs to the more restricted CLP, CMP, GMP, and MEP and then through early lineage-committed progenitors to mature T, B, NK, myeloid, and erythroid lineage cells.

MATERIALS AND METHODS

SCL mRNA Is Expressed in CD34 CD38– HSCs from Human BM6 D; d$ X3 l- _% X# |
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Given that SCL is required for the production of murine HSCs, we first examined the expression of human SCL in HSCs and in progenitor populations isolated from normal BM. CD34 CD38– HSCs and CD34 CD38  progenitors were FACS-sorted using sort gates shown in Figure 1A. SCL mRNA was detectable by reverse transcription (RT)–PCR analysis in CD34 CD38– HSCs isolated from human BM (Fig. 1B). SCL mRNA was also detected in the CD34 CD38  BM progenitor population (Fig. 1B), which includes a mixture of lymphoid, myeloid, and erythroid progenitors. To determine if SCL expression in this mixed progenitor population was due entirely to erythroid-committed cells, we also examined SCL mRNA expression in FACS-sorted CD34 CD38  progenitors that lacked expression of the erythroid lineage marker glycophorin A (CD34 CD38 GlyA–). SCL message was detectable in CD34 CD38–GlyA– cells, although at lower levels than in the CD34 C38  population (Fig. 1B).

Figure 1. SCL expression in human BM hematopoietic stem cell and progenitor populations. Human CD34 CD38– (gate R2) and CD34 CD38  (gate R3) cells were (A) fluorescence-activated cell–sorted from cells falling within progenitor/lymphoid light scatter (gate R1) in CD34 -enriched BM and (B) assessed by RT-PCR for expression of SCL and ?2-microglobulin (?2m) as a control for cDNA quality. In separate experiments, (C, D) CD34 CD38– or (E) CD34 CD38  populations were subjected to more stringent selection criteria, as shown and described in the Results section. (F, G): Progenitor populations isolated using indicated gates were assessed by RT-PCR. To provide a semiquantitative assessment of relative SCL expression, RT-PCR was performed on varying numbers of sorted cells, and RT-PCR products were removed after varying numbers of PCR cycles as indicated. Note that cell numbers do not apply to positive control K562 cells. Abbreviations: BM, bone marrow; FITC, fluorescein isothiocyanate; FSC, forward scatter; PE, phycoerythrin; RT-PCR, reverse transcription–polymerase chain reaction; SCL, stem cell leukemia; SSC, side scatter.* }& ?9 l8 n. v% a$ T, r

We then took several steps to ensure that the SCL mRNA detected in the BM HSC and progenitor populations was not due to lineage-committed cells or to low purity of the FACS sort in general. First, CD34 CD38– BM progenitors were isolated based on the absence of hematopoietic lineage markers (Lin–CD34 CD38–, gates shown in Figs. 1A and 1C: R1, R2, and R4) and then resorted a second time to ensure purity. RT-PCR analysis of 1,500 double-sorted cells at 35, 38, and 40 cycles (Fig. 1F) shows that SCL transcripts were present in highly purified Lin–CD34 CD38– HSCs isolated from human BM. Next, to preclude the possibility that the SCL expression we detected was due to contamination with very early erythroid-committed cells, we sorted HSCs and progenitors that were negative for both the erythroid lineage marker glycophorin A and the transferrin receptor CD71. (CD71 is thought to be expressed on erythroid-committed cells before glycophorin A .) We isolated CD34 CD38–GlyA–CD71– (gates shown in Figs. 1A and 1D: R1, R2, and R5) and CD34  CD38  GlyA–CD71– (gates shown in Figs. 1A and 1E: R1, R3, and R5) cells. SCL transcripts were detectable by RT-PCR in both populations (Fig. 1G), although depletion of cells expressing erythroid markers markedly reduced the expression level in CD34 CD38  populations.
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Expression of SCL During Lymphoid Differentiation

SCL was initially identified in a leukemia with both lymphoid and myeloid potential  and later associated with T-ALL . Recent murine studies of SCL conditional mutants suggest that SCL may promote B versus T lymphopoiesis . Given these links between SCL and lymphopoiesis, we next determined whether SCL expression is extinguished during normal lymphoid differentiation. To address this question, we examined SCL expression in developmentally sequential populations of lymphoid differentiation intermediates isolated from human umbilical CB and thymus.) `) g" s5 r- j" y3 H

From human CB, HSCs (CD34 CD38–Lin–CD7–) and CLPs (CD34 CD38–Lin–CD7 ) were sorted as shown in Figures 2A and 2B. RT-PCR showed that in CB, as in BM, HSCs express SCL message (Fig. 2D, left panel). SCL message was also detectable in CLPs but downregulated relative to HSCs (Fig. 2D, left panel). Using sort gates shown in Figure 2C, CD34 CD19  proB cells and more mature CD34–CD19  B lineage cells were also FACS-sorted from human CB. SCL transcripts were not detected in CD34 CD19  pro-B cells or CD34–CD19  B lineage cells isolated from CB (Fig. 2D, right panel). The complete absence of detectable SCL transcripts in CD19  B lineage cells provides evidence that the SCL detected in the CLP population was not the result of contamination from more common B cell progenitors. Thus, SCL mRNA is expressed in pluripotent HSCs, down-regulated in the CLP population after lymphoid commitment, and completely lost by the time lymphoid progenitors acquire CD19 and commit to B lymphopoiesis.- Q4 @8 [! f  F% W' p% d6 R7 d
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Figure 2. SCL expression in lymphoid and progenitor populations isolated from human CB. (A): CD34 -enriched CB cells that fall within progenitor/lymphoid light scatter (shown as gate R1 in Fig. 1A), (B) human HSC (gates R2 R3) and CLP (gates R2 R4) populations, as well as (B) B cells (gate R5) and pro-B cells (gate R6) were FACS-sorted. (D): Populations gated as shown were FACS-sorted, resorted to ensure purity, and then assessed by RT-PCR for expression of SCL and ?2-microglobulin (?2m) as a control for cDNA quality. Results are representative of three or more independent experiments. To provide a semiquantitative assessment of SCL expression, RT-PCR products were removed after varying numbers of PCR cycles as indicated. Note that cell numbers do not apply to positive control K562 cells. Abbreviations: APC, allophycocyanin; CB, cord blood; CLP, common lymphoid progenitor; ECD, energy-coupled dye; FACS, fluorescence-activated cell sorting; FITC, fluorescein isothiocyanate; HSC, hematopoietic stem cell; PE, phycoerythrin; RT-PCR, reverse transcription–polymerase chain reaction; SCL, stem cell leukemia.
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To determine SCL expression during T-lymphocyte differentiation, we isolated T-cell precursor populations from human thymus. Very early thymic T-cell progenitors were obtained by FACS-sorting Lin–CD34 CD7  from human thymus that had been enriched for CD34  cells by magnetic separation (sort gates shown in Figs. 3A and 3B). We also isolated the classic CD34– T-cell precursor populations, double-positive (CD4 CD8 ), CD4 single-positive (CD4 CD8–), and CD8 single-positive (CD4–CD8 ), from total thymus using sort gates as shown in Figure 3C. All populations were isolated based on the absence of glycophorin A (gate not shown) and double-sorted to ensure purity. RT-PCR analysis showed that SCL expression is absent in all thymic T-cell precursor populations, including the very early Lin–CD34 CD7  thymic progenitors (Fig. 3D).
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Figure 3. Expression of SCL in thymic progenitor populations. From human thymic cells enriched for CD34 expression by magnetic separation, cells that fall within progenitor/lymphoid light scatter (gate R1 as shown in Fig. 1A), were FACS-sorted using (A) gate R2 and (B) gate R3 to isolate Lineage–CD34 CD7  thymic progenitors. (C): Double-positive (gate R5) and single-positive (gate R4 or gate R6) thymic precursor populations were FACS-sorted from total thymus cells that fall within progenitor/lymphoid light scatter (gate R1 as shown in Fig. 1A). (D): Sorted populations were assessed by RT-PCR for expression of SCL and ?2-microglobulin (?2m) as a control for cDNA quality. Results are representative of three or more independent experiments. To provide a semiquantitative assessment of SCL expression, RT-PCR products were removed after varying numbers of PCR cycles as indicated. Note that cell numbers do not apply to positive control K562 cells. Abbreviations: APC, allophycocyanin; ECD, energy-coupled dye; FACS, fluorescence-activated cell sorting; FITC, fluorescein isothiocyanate; PE, phycoerythrin; RT-PCR, reverse transcription–polymerase chain reaction; SCL, stem cell leukemia.

Expression of SCL During Myeloid and Erythroid Differentiation

SCL has been postulated to play a role in lineage commitment . Therefore, we examined SCL expression at critical branch points in myeloerythroid differentiation. CMP, GMP, and MEP populations were isolated from human CD34 -enriched CB using recently defined surface immunophenotypes  (sort gates shown in Figs. 4A and 4B). SCL transcripts were easily detectable in the CMP and MEP populations, both of which possess erythroid differentiation potential (Fig. 4E, left panel). SCL mRNA was detectable but markedly downregulated in the GMP (Fig. 4E, left panel), a population that is restricted to nonerythroid lineages.4 l+ p% I7 S9 S* U$ C
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Figure 4. SCL expression in myeloid and erythroid progenitors isolated from human CB. (A): Lineage–CD34 CD38  cells were FACS-sorted from CD34 -enriched CB cells based on gates R1, R2, and R3 as shown. (B): Sorted cells were stained with indicated markers for a second FACS to isolate human CMP, GMP, and MEP populations as described in Materials and Methods and Results. (C): M-CSFR  cells (gate R4) were FACS-sorted from CB mononuclear cells that fall within a living cell light scatter gate (gate not shown). (D): Nucleated glycophorin-A  (GlyA ) CD34– (gate R5) and GlyA  CD34  (gate R6) cells were FACS-sorted from human CD34 -enriched CB cells falling within a small progenitor/lymphoid light scatter gate (gate not shown). (E): Sorted populations were assessed by RT-PCR for expression of SCL and ?2-microglobulin (?2m) as a control for cDNA quality. Results are representative of two or more independent experiments. To provide a semiquantitative assessment of SCL expression, RT-PCR products were removed after varying numbers of PCR cycles as indicated. Note that cell numbers do not apply to positive control K562 cells. Abbreviations: APC, allophycocyanin; CB, cord blood; CMP, common myeloid progenitor; FACS, fluorescence-activated cell sorting; FSC, forward scatter; GMP, granulocyte/monocyte progenitor; IL, interleukin; MEP, megakaryocyte/erythroid progenitor; M-CSFR, monocyte colony stimulating factor receptor; PE, phycoerythrin; PerCP, peridinin chlorophyll protein; RT-PCR, reverse transcription–polymerase chain reaction; SCL, stem cell leukemia; SSC, side scatter.
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Next we examined myeloid and erythroid progenitors downstream of the erythroid-myeloid branch point. To determine if SCL is expressed after commitment to monocyte differentiation, we FACS-sorted myeloid precursors from CB based on expression of the M-CSFR as shown in Figure 4C. To isolate early erythroid-committed precursors, we FACS-sorted nucleated erythroid lineage cells that were glycophorin A CD34 , along with more mature glycophorin A  CD34–cells (Fig.4D). SCL transcripts were completely undetectable in M-CSF-R  CB cells after 40 cycles of PCR (Fig. 4E, right panel). In contrast, SCL transcripts were readily detectable in glycophorin A  CD34  and glycophorin A  CD34– cells (Fig. 4E, right panel).4 A# f% ^# h6 ^0 T6 p: o  Y1 b

SCL Expression in Mature Hematopoietic Cells4 w" `1 `3 B+ `" A& B& l

To determine SCL expression in mature cells of the various hematopoietic lineages, we isolated cells based on expression of lineage-specific surface markers or combinations of markers as shown in Figure 5. RT-PCR analysis showed that SCL transcripts continued to be expressed in nucleated glycophorin A  CD34– erythroid lineage cells isolated from BM (Fig. 5), as well as CB (Fig. 4E). SCL was not detectable in mature B cells, NK cells, CD4  T cells, CD66B  granulocytes, or CD14 CD11B  monocytes (Fig. 5).
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Figure 5. Expression of SCL in mature hematopoietic cells. Mature T, B, and natural killer (NK) cells, monocytes (M), granulocytes (G), and nucleated erythroid lineage cells (E) were FACS-sorted from human peripheral blood, bone marrow (E only), or cord blood (G only) based on expression of lineage-specific markers or combinations of markers as shown. Sorted populations were assessed by reverse transcription–polymerase chain reaction for expression of SCL and ?2-microglobulin (?2m) as a control for cDNA quality. Results are representative of two or more independent experiments. Note that cell numbers do not apply to positive control K562 cells. Abbreviations: FACS, fluorescence-activated cell sorting; SCL, stem cell leukemia.

DISCUSSION

SCL mRNA is abundant in all hematopoietic populations with erythroid potential, including HSCs, multipotential progenitors, CMPs, MEPs, and nucleated erythroid lineage cells. SCL mRNA was rapidly downregulated in the CLP and GMP populations that lacked erythroid potential. SCL was not expressed in immature cells of nonerythroid lineages, including pro-B cells, early thymic progenitors, and myeloid precursors expressing the M-CSF receptor. SCL expression was also absent from the mature cells of the nonerythroid lineages. Although low levels of SCL message were detected in lymphoid- and myeloid-restricted progenitors, our studies show that abundant SCL expression is normally tightly linked with erythroid differentiation potential (Fig. 6).
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ACKNOWLEDGMENTS. e  _, n0 b! j4 M& w; ]' ], @

* These authors contributed equally.

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