Hematopoietic Fingerprints: An Expression Database of Stem Cells and Their Progeny

Chambers, Stuart M.; Boles, Nathan C.; Lin, Kuan Yin K.; Tierney, M.; Bowman, Teresa V.; Bradfute, Steven B.; Chen, Alice J.; Merchant, Akil; Sirin, Olga; Weksberg, David C.; Merchant, Mehveen G.; Fisk, C. Joseph; Shaw, Chad A.; Goodell, Margaret A.

doi:10.1016/j.stem.2007.10.003

Cited by 282 publications

(354 citation statements)

References 46 publications

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“…The amount of antibody produced, both IgM and IgG1, was not CD248 dependent. This taken together with data that show all murine haematopoietic cells examined so far do not express CD248 mRNA [16] suggest that CD248 KO mice are unlikely to have defects in the motility of cells at the injection site and/ or in lymphoid cells migrating into and out of the pLN during the NP-CGG response. Our data therefore suggest that CD248 does not play a role in regulating T-and B-cell-dependent immune responses in pLN to NP-CGG.…”

Section: Cd248 Is Involved In Pln Expansion But Not Antibody Productimentioning

confidence: 73%

The pericyte and stromal cell marker CD248 (endosialin) is required for efficient lymph node expansion

et al. 2010

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CD248 is a cell surface receptor that specifically identifies fibroblasts and pericytes during development and in association with cancer and inflammation. However, its function is poorly defined and its role in lymphoid organs not studied. Here, we used (4-hydroxy-3-nitrophenyl)acetyl chicken c-globulin immunisation and mice lacking CD248 to study whether CD248 modulates popliteal LN (pLN) expansion and subsequent immune responses. We have found that CD248 is required for complete pLN expansion but not for co-ordination of B and T cell compartmentalisation or antibody production following (4-hydroxy-3-nitrophenyl)acetyl chicken c-globulin immunisation. In vitro, we show that CD248 expression in human MG63 stromal cells and mouse embryonic fibroblasts leads to a pro-proliferative and pro-migratory phenotype. This correlates with a proliferating CD248 1 population observed in vivo during pLN expansion. Taken together, these data highlight a role for CD248 in secondary lymphoid organ remodelling during adaptive immune responses.Key words: CD248 . Endosialin . Fibroblast . Lymphoid tissue . Stromal cells IntroductionDuring an immune response, secondary lymphoid organs (SLO) expand significantly. However, mechanisms that regulate this have been relatively understudied with leucocyte accumulation rather than stromal cell expansion being the focus. Logic dictates that there has to be co-ordinated expansion of tissue structure to accommodate the rapidly expanding leucocyte populations. This expansion includes not only an intricate network of fibroblasts that provide an important structural scaffold but also the formation of new blood and lymph vessels to oxygenate and allow transport of lymphocytes into and out of the organ [1].CD248/endosialin is a relatively new marker for a subset of stromal cells in developing tissues. It is a member of an emerging transmembrane protein family implicated in tissue remodelling and repair, which includes CD141 and CD93 [2,3] 1884expressed on fibroblasts and pericytes during development and in tumour-associated stroma [4][5][6][7]. An important role for CD248 within tumour stroma has been highlighted in CD248-deficient mice; abdominal tumours implanted into mice lacking CD248 demonstrated reduced growth, invasion and metastasis [8]. This, coupled with the finding that CD248 expression is regulated by hypoxia inducible factor-2a [9], suggests that CD248 may provide an important link between hypoxia and tissue remodelling allowing synchronisation of these processes.We have previously proposed a role for CD248 in development and infection-dependent activation of SLO stroma [10]. Whether CD248 is required for tissue remodelling was not explored nor was its function. Therefore, to more fully understand the requirements for CD248 during remodelling, we compared the degree of popliteal LN (pLN) expansion in WT and CD248 KO mice following immunisation with (4-hydroxy-3-nitrophenyl)acetyl chicken g-globulin (NP-CGG). The ability of CD248 to regulate cell migration and proliferation in vitro w...

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Section: Cd248 Is Involved In Pln Expansion But Not Antibody Productimentioning

confidence: 73%

The pericyte and stromal cell marker CD248 (endosialin) is required for efficient lymph node expansion

et al. 2010

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“…This orientation-dependent effect may be related to the balance of the divergent transcriptional activity of both promoters. Whereas HNRPA2B1 transcripts are detected at high levels in most cell types including peripheral blood mononuclear cells, 23,45 transcript levels from the CBX3 promoter are two-to fivefold lower in hematopoietic tissues. Indeed, the level of eGFP expression was higher in PLB985 clones transduced with the UfMEW vector as compared with that observed in UrMEW-transduced cells, as estimated from the MFI per VCN (Figure 2a).…”

Section: Discussionmentioning

confidence: 97%

Physiological regulation of transgene expression by a lentiviral vector containing the A2UCOE linked to a myeloid promoter

et al. 2011

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Protection against epigenetic silencing is a desirable feature of future gene therapy vectors, in particular for those applications in which transgene expression will not confer growth advantage to gene-transduced cells. The ubiquitous chromatin opening element (UCOE) consisting of the methylation-free CpG island encompassing the dual divergently transcribed promoters of the human HNRPA2B1-CBX3 housekeeping genes (A2UCOE) has been shown to shield constitutive active heterologous promoters from epigenetic modifications and chromosomal position effects. However, it is unclear if this element can be used to improve expression from tissue-specific enhancer/promoters, while maintaining tissue specificity in hematopoietic cells. Here, we evaluated the potential of the A2UCOE in combination with the myeloid-specific myeloid related protein 8 (MRP8) promoter to target transgene expression specifically to myeloid cells in vitro and in vivo from a self-inactivating lentiviral vector. The inclusion of the A2UCOE did not interfere with specific upregulation of MRP8 promoter activity during myeloid differentiation and mediated sustained and vector copy-dependent expression in myeloid cells. Notably, the A2UCOE did not protect the MRP8 promoter from methylation in the P19 embryonal carcinoma cell line, suggesting that this element maintains the inherent epigenetic state and transcriptional activity of cellular promoters in their native configuration. Thus, the A2UCOE could represent a useful protective genetic element in gene therapy vectors, ensuring physiological transcriptional regulation of tissue-specific promoters independent of the chromosomal integration site.

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“…Because SirT1 is expressed at high levels in HSCs, 45 resveratrol could stimulate SirT1 activity and directly enhance SirT1-mediated DNA repair. 29,30 However, the function of SirT1 in HSC remains elusive.…”

Section: Discussionmentioning

confidence: 99%

Fancd2 −/− mice have hematopoietic defects that can be partially corrected by resveratrol

Zhang

Marquez-Loza

Eaton

et al. 2010

Blood

105

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Progressive bone marrow failure is a major cause of morbidity and mortality in human Fanconi Anemia patients. In an effort to develop a Fanconi Anemia murine model to study bone marrow failure, we found that Fancd2 ؊/؊ mice have readily measurable hematopoietic defects. Fancd2 deficiency was associated with a significant decline in the size of the c-Kit ؉ Sca-1 ؉ Lineage ؊ (KSL) pool and reduced stem cell repopulation and spleen colony-forming capacity. Fancd2 ؊/؊ KSL cells showed an abnormal cell cycle status and loss of quiescence. In addition, the supportive function of the marrow microenvironment was compromised in Fancd2 ؊/؊ mice. Treatment with Sirt1-mimetic and the antioxidant drug, resveratrol, maintained Fancd2 ؊/؊ KSL cells in quiescence, improved the marrow microenvironment, partially corrected the abnormal cell cycle status, and significantly improved the spleen colony-forming capacity of Fancd2 ؊/؊ bone marrow cells. We conclude that Fancd2 ؊/؊ mice have readily quantifiable hematopoietic defects, and that this model is well suited for pharmacologic screening studies. IntroductionFanconi anemia (FA) is a rare, autosomal, recessive genetic disorder associated with severe birth defects, cancer predisposition, and bone marrow failure. Thirteen causative genes (FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG/XRCC9, FANCI, FANCL/PHF9/Pog, FANCJ/BRIP1/BACH1, FANCM/Hef, and FANCN/ PALB2) have been identified and cloned to date, and the encoded proteins are believed to work together in a common DNA damageresponse pathway to maintain genomic integrity and protect the genome from DNA damage induced by cross-linking agents. 1,2 Although deficiency in DNA cross-link repair renders all FA cells susceptible to cross-linking agents, bone marrow is the most affected organ system. Mutations in any of the different FA genes almost universally lead to bone marrow failure, which is the primary cause of mortality in FA. 3 The pathogenesis of bone marrow failure in FA remains elusive. Mutations in several genes involved in DNA damage repair, including Atr, XPD, and Ercc1, caused either hematopoietic stem cell (HSC) loss or impaired HSC function under conditions of stress. [4][5][6] These studies suggest that the maintenance of genome integrity is critical for HSC survival and function. However, the extent to which genotoxicity, resulting from impaired DNA damage repair, contributes to bone marrow failure in FA is unclear. 7 Other pathways associated with hematopoietic failure, such as altered cytokine signaling, may also contribute to FA pathogenesis. 8,9 For example, levels of proapoptotic cytokines tumor necrosis factor-␣ (TNF-␣) and interferon-␥ (IFN-␥) are elevated in FA lymphocytes, bone marrow cells, and FA patient serum samples. 10-12 FA bone marrow cells (at least of the C complementation group) are also hypersensitive to these cytokines and undergo apoptosis when exposed to even low levels of them. [13][14][15] To better understand FA, multiple murine knockout models, includingand Fancl Ϫ/Ϫ m...

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Hematopoietic Fingerprints: An Expression Database of Stem Cells and Their Progeny

Cited by 282 publications

References 46 publications

The pericyte and stromal cell marker CD248 (endosialin) is required for efficient lymph node expansion

The pericyte and stromal cell marker CD248 (endosialin) is required for efficient lymph node expansion

Physiological regulation of transgene expression by a lentiviral vector containing the A2UCOE linked to a myeloid promoter

Fancd2 −/− mice have hematopoietic defects that can be partially corrected by resveratrol

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