Bone marrow stromal cells induce myeloid and lymphoid development of the sorted hematopoietic stem cells in vitro

Okuyama, Ryuhei; Koguma, Masahito; Yanai, Nobuaki; Obinata, Masuo

doi:10.1182/blood.v86.7.2590.2590

Cited by 26 publications

(7 citation statements)

References 27 publications

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“…Yolk sac cells were inoculated into 0.8% methylcellulose and cultured in the presence of erythropoietin (2 U/ml) and stem cell factor (SCF; 50 ng/ml) (Okuyama et al ., 1995), and the numbers of colonies (colony‐forming unit‐erythroid, CFU‐E) formed were counted.…”

Section: Methodsmentioning

confidence: 99%

Heme deficiency in erythroid lineage causes differentiation arrest and cytoplasmic iron overload

Nakajima

Takahashi

Harigae

et al. 1999

EMBO J

101

100

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Erythroid 5-aminolevulinate synthase (ALAS-E) catalyzes the first step of heme biosynthesis in erythroid cells. Mutation of human ALAS-E causes the disorder X-linked sideroblastic anemia. To examine the roles of heme during hematopoiesis, we disrupted the mouse ALAS-E gene. ALAS-E-null embryos showed no hemoglobinized cells and died by embryonic day 11.5, indicating that ALAS-E is the principal isozyme contributing to erythroid heme biosynthesis. In the ALAS-E-null mutant embryos, erythroid differentiation was arrested, and an abnormal hematopoietic cell fraction emerged that accumulated a large amount of iron diffusely in the cytoplasm. In contrast, we found typical ring sideroblasts that accumulated iron mostly in mitochondria in adult mice chimeric for ALAS-E-null mutant cells, indicating that the mode of iron accumulation caused by the lack of ALAS-E is different in primitive and definitive erythroid cells. These results demonstrate that ALAS-E, and hence heme supply, is necessary for differentiation and iron metabolism of erythroid cells.

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Section: Methodsmentioning

confidence: 99%

Heme deficiency in erythroid lineage causes differentiation arrest and cytoplasmic iron overload

Nakajima

Takahashi

Harigae

et al. 1999

EMBO J

101

100

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“…Its immortalizing activity is based upon its interaction with the retinoblastoma protein and p53, and their regulators p21 CIP1/WAF1 and p16 INK4 , and the recently described tumor suppressor gene SEN6 leading to extended proliferation (Smith and Pereira-Smith, 1996). Rather than using the commercially available 'Immorto' mouse (Jat et al, 1991) or the transient transgenic approach (Okuyama et al, 1995a;Okuyama et al, 1995b), we generated two new mouse lines, Tag5 and Tag11, that express the tsA58 gene under the control of the β-actin or PGK gene promoters.…”

Section: Discussionmentioning

confidence: 99%

Embryonal subregion-derived stromal cell lines from novel temperature-sensitive SV40 T antigen transgenic mice support hematopoiesis

Oostendorp

Medvinsky

Kuşadasi

et al. 2002

Journal of Cell Science

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Throughout life, the hematopoietic system requires a supportive microenvironment that allows for the maintenance and differentiation of hematopoietic stem cells (HSC). To understand the cellular interactions and molecules that provide these functions, investigators have previously established stromal cell lines from the late gestational stage and adult murine hematopoietic microenvironments. However, the stromal cell microenvironment that supports the emergence, expansion and maintenance of HSCs during mid-gestational stages has been largely unexplored. Since several tissues within the mouse embryo are known to harbor HSCs (i.e. aortagonads-mesonephros, yolk sac, liver), we generated numerous stromal cell clones from these mid-gestational sites. Owing to the limited cell numbers,isolations were performed with tissues from transgenic embryos containing the ts SV40 Tag gene (tsA58) under the transcriptional control of constitutive and ubiquitously expressing promoters. We report here that the growth and cloning efficiency of embryonic cells (with the exception of the aorta) is increased in the presence of the tsA58 transgene. Furthermore, our results show that the large panel of stromal clones isolated from the different embryonal subregions exhibit heterogeneity in their ability to promote murine and human hematopoietic differentiation. Despite our findings of heterogeneity in hematopoietic growth factor gene expression profiles, high-level expression of some factors may influence hematopoietic differentiation. Interestingly, a few of these stromal clones express a recently described chordin-like protein, which is an inhibitor of bone morphogenic proteins and is preferentially expressed in cells of the mesenchymal lineage.

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“…Therefore, to further clarify the MHC preference between HSCs and stromal cells and investigate the mechanisms underlying the preference, we analyzed the cobblestone colony formation of HSCs under the monolayers of the MHC‐matched and ‐mismatched stromal cells derived from fetal bones. Since the cobblestone colony is composed solely of cells which are phenotypically identical to HSCs [52, 53], and since the cobblestone area‐forming cells differentiate not only into myeloid and erythroid but also lymphoid cells [54, 55], the cobblestone assay permits the direct measurement of differentiating HSCs in the context of the interaction with stromal cells. In the present study, we have shown that two to five times more HSCs are required for obtaining 50% cobblestone colony formation when BMCs were added to the MHC‐mismatched stromal cell layers (Table 2).…”

Section: Discussionmentioning

confidence: 99%

Major Histocompatibility Complex Restriction Between Hematopoietic Stem Cells and Stromal Cells In Vitro

et al. 2001

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We have previously found that a significant number of hematopoietic progenitors accumulate in engrafted bones with the same major histocompatibility complex (MHC) as the transplanted bone marrow cells. In the present study, to further clarify the MHC restriction between hematopoietic stem cells (HSC) and microenvironment, we carried out cobblestone colony formation assays by culturing HSCs with MHC-matched or -mismatched stromal cell monolayers. The formation of cobblestone colonies under MHC-mismatched stromal cells significantly decreased in comparison with MHC-matched stromal cells. However, the decrease in cobblestone colony formation under MHC-mismatched stromal cells was not significant when using MHC class I-deficient HSC or stromal cells. Taken together with the results using B10 congenic strains, it is suggested that the MHC preference is restricted by MHC class Ia molecules. Treatment with monoclonal antibodies (mAbs) against MHC class Ia molecules of stromal cell phenotypes significantly enhanced the cobblestone colony formation, whereas treatment with mAbs against HSC phenotypes significantly inhibited it. The expression of cytokines to promote hematopoiesis was enhanced by the mAbs against stromal cell phenotypes. The enhancement of cytokine expression was also observed when stromal cells and HSCs were MHC-matched. These results suggest that signaling via the MHC molecules augments stromal cell activity and elicits the MHC restriction.

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Bone marrow stromal cells induce myeloid and lymphoid development of the sorted hematopoietic stem cells in vitro

Cited by 26 publications

References 27 publications

Heme deficiency in erythroid lineage causes differentiation arrest and cytoplasmic iron overload

Heme deficiency in erythroid lineage causes differentiation arrest and cytoplasmic iron overload

Embryonal subregion-derived stromal cell lines from novel temperature-sensitive SV40 T antigen transgenic mice support hematopoiesis

Major Histocompatibility Complex Restriction Between Hematopoietic Stem Cells and Stromal Cells In Vitro

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