scholarly journals Leukotriene B4, an activation product of mast cells, is a chemoattractant for their progenitors

2005 ◽  
Vol 201 (12) ◽  
pp. 1961-1971 ◽  
Author(s):  
Charlotte L. Weller ◽  
Sarah J. Collington ◽  
Jeremy K. Brown ◽  
Hugh R.P. Miller ◽  
Adam Al-Kashi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Bone Marrow Cells ◽  
Marrow Cell ◽  
The Body ◽  
Active Principle ◽  
Human Cord Blood ◽  
Hematopoietic Stem

Mast cells are tissue-resident cells with important functions in allergy and inflammation. Pluripotential hematopoietic stem cells in the bone marrow give rise to committed mast cell progenitors that transit via the blood to tissues throughout the body, where they mature. Knowledge is limited about the factors that release mast cell progenitors from the bone marrow or recruit them to remote tissues. Mouse femoral bone marrow cells were cultured with IL-3 for 2 wk and a range of chemotactic agents were tested on the c-kit+ population. Cells were remarkably refractory and no chemotaxis was induced by any chemokines tested. However, supernatants from activated mature mast cells induced pronounced chemotaxis, with the active principle identified as leukotriene (LT) B4. Other activation products were inactive. LTB4 was highly chemotactic for 2-wk-old cells, but not mature cells, correlating with a loss of mRNA for the LTB4 receptor, BLT1. Immature cells also accumulated in vivo in response to intradermally injected LTB4. Furthermore, LTB4 was highly potent in attracting mast cell progenitors from freshly isolated bone marrow cell suspensions. Finally, LTB4 was a potent chemoattractant for human cord blood–derived immature, but not mature, mast cells. These results suggest an autocrine role for LTB4 in regulating tissue mast cell numbers.

scholarly journals CD34+ human marrow cells that express low levels of Kit protein are enriched for long-term marrow-engrafting cells

Blood ◽  
1996 ◽  
Vol 87 (10) ◽  
pp. 4136-4142 ◽  
Author(s):  
I Kawashima ◽  
ED Zanjani ◽  
G Almaida-Porada ◽  
AW Flake ◽  
H Zeng ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Marrow Cell ◽  
In Utero ◽  
Fetal Sheep ◽  
Hematopoietic Stem ◽  
Show Evidence ◽  
Marrow Cells

Using in utero transplantation into fetal sheep, we examined the capability of human bone marrow CD34+ cells fractionated based on Kit protein expression to provide long-term in vivo engraftment. Twelve hundred to 5,000 CD34+ Kit-, CD34+ Kit(low), and CD34+ Kit(high) cells were injected into a total of 14 preimmune fetal sheep recipients using the amniotic bubble technique. Six fetuses were killed in utero 1.5 months after bone marrow cell transplantation. Two fetuses receiving CD34+ Kit(low) cells showed signs of engraftment according to analysis of CD45+ cells in their bone marrow cells and karyotype studies of the colonies grown in methylcellulose culture. In contrast, two fetuses receiving CD34+ Kit(high) cells and two fetuses receiving CD34+ Kit- cells failed to show evidence of significant engraftment. Two fetuses were absorbed. A total of six fetuses receiving different cell populations were allowed to proceed to term, and the newborn sheep were serially examined for the presence of chimerism. Again, only the two sheep receiving CD34+ Kit(low) cells exhibited signs of engraftment upon serial examination. Earlier in studies of murine hematopoiesis, we have shown stage-specific changes in Kit expression by the progenitors. The studies of human cells reported here are in agreement with observations in mice, and indicate that human hematopoietic stem cells are enriched in the Kit(low) population.

Identification of Bipotent Basophil/Mast Cell Progenitors in Adult Murine Hematopoiesis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 633-633
Author(s):  
Yojiro Arinobu ◽  
Hiromi Iwasaki ◽  
Michael F. Gurish ◽  
Shinichi Mizuno ◽  
Hirokazu Shigematsu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Cell Fate ◽  
Bone Marrow Cells ◽  
Cell Lineage ◽  
Primary Role ◽  
Peripheral Tissues ◽  
Fate Decision

Abstract Basophils and mast cells are multifunctional hematopoietic effectors that co-operate to mount a variety of allergic and innate immune responses. Their origin and developmental relationships, however, have not yet been resolved, and remain as one of the major issues in the biology of hematopoiesis. Here we report that progenitors bipotent for basophils and mast cells(basophil/mast cell progenitors: BMCPs) are prospectively isolatable within murine spleen. We have shown that the β7-integrin(β7) is an essential molecule for tissue-specific homing of putative precursors for intestinal mast cells (J Exp Med194:1243, 2001). To identify a candidate population that seeds intestinal progenitors for mast cells, we searched for β7+ cells in the bone marrow and the spleen. Lin−c-Kit+ spleen cells contained a fraction of cells expressing β7 at high levels. They also expressed FcγRII/III, but the majority of these cells did not express FcεRIα. These Lin−c-Kit+FcγRII/III+β7hiFcεRIα−/locells exclusively differentiated into mature mast cells and basophils. Strikingly, single Lin−c-Kit+FcγRII/III+β7hiFcεRIα−/locells formed colonies containing both basophils and mast cells as well as pure mast cell or basophil colonies. We thus named these cells as BMCPs. In 2-day cultures, purified BMCPs upregulated FcεRIα, giving rise to Lin−CD34+FcεRIαhic-Kit+ and Li− CD34+FcεRIαhic-Kit− blastic cell populations, and they differentiated exclusively into mast cells and basophils, respectively. Based on this phenotype, we searched for precursors committed to either lineage in vivo. The Lin−CD34+ bone marrow cells contained FcεRIαhic-Kit−cells, which differentiated exclusively into basophils. We named this population as basophil progenitors (BaPs). Since mast cell progenitors(MCPs) were not isolatable as a distinct population in the bone marrow or the spleen, we searched for MCPs in the intestine. We newly identified CD45+Li− CD34+β7hiFcεRIαlocells in the intestine, and these cells exclusively formed pure mast cell colonies, which were named as intestinal MCPs. Since the expression of C/EBPα was dramatically increased in BaPs but was downregulated in MCPs, we hypothesized that it plays a key role in the basophil versus the mast cell lineage commitment. To test this hypothesis, we disrupted or overexpressed C/EBPα at the BMCP stage. BMCPs disrupted with C/EBPα gave rise exclusively to mast cells, while, BMCPs overexpressing C/EBPα differentiated mainly into basophils, suggesting that C/EBPα plays a primary role in deciding the basophil vs. mast cell fate at the BMCP stage. Thus, differentiation of the BMCPs into committed progeny may lead to selective migration, BaPs to the bone marrow or MCPs to peripheral tissues, and this fate decision is controlled principally by C/EBPα. These newly identified progenitors should be useful to analyze the mechanism of commitment into each of these lineages, and could also be therapeutic targets for a variety of allergic and autoimmune disorders.

A Novel Strategy for Expanding Primitive Leukemic Cells from Chronic Phase CML Patients by Forced Overexpression of a NUP98-HOXA10 Homeodomain Fusion Gene.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1078-1078
Author(s):  
Ivan Sloma ◽  
Suzan Imren ◽  
Yun Zhao ◽  
Keith Humphries ◽  
Connie J. Eaves
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Fusion Gene ◽  
Low Frequency ◽  
Chronic Phase ◽  
Leukemic Cells ◽  
Human Cord Blood ◽  
Hematopoietic Stem

Abstract Analysis of the leukemic stem cell compartment in CML patients with chronic phase disease remains a major challenge. This is due to the usually low frequency of these cells in the bone marrow and blood of most patients regardless of the WBC count and the fact that they are typically outnumbered by normal hematopoietic stem cells from which they cannot be currently separated. Moreover, thus far it has not been possible to identify conditions for their selective expansion in vitro or in vivo. To pursue this goal, we have begun to explore the effects of certain HOX gene-containing constructs on primitive chronic phase CML cells based on previous evidence that these genes markedly enhance the expansion of primitive normal murine and human cord blood cell numbers without inducing leukemia. Lineage-negative peripheral blood or bone marrow cells from 3 chronic phase CML patients (with >93%, <20% and <6% Ph+ LTC-ICs by G-banding karyotyping) were pre-stimulated overnight in a medium containing a serum substitute and 100 ng/ml hSteel Factor (SF), 100 ng/ml hFlt3-ligand and 20 ng/ml each of hIL-3, hIL-6 and hG-CSF. Cells were then exposed to a lenti-PGK-GFP virus with or without an upstream MDUS-NUP98-HOXA10 homeodomain (HD) element for 5 hours in the same medium. After removal of the virus, the cells were maintained in culture under the same conditions for 2 more days to allow full expression of the transduced genes. At this point, both cultures contained the same number of total cells, GFP+ cells and clonogenic progenitors (BFU-E + CFU-GM + CFU-GEMM); i.e., 2.2±0.5 x105 vs 2.2±0.6 x105 total cells, 1.0±0.2 x105 vs 1.3±0.3 x105 GFP+ cells, 3.6±1.7 x104 vs 3.4±1.7 x104 total CFCs and 1.7±0.9 x104 vs 2.4±1.3 x104 GFP+ CFCs per 105 starting lin- cells. However, after the 2-day post-transduction, cells had been maintained for 6 weeks in longterm cultures (LTCs) containing murine stromal cells producing hIL-3, hSF and hG-CSF, we noted a markedly higher (4 to 74-fold) output of CFCs from the NUP98-HOXA10HD-transduced cells. Moreover, whereas the proportion of GFP+ CFCs in the 2-day post-transduction cultures was on average only 31% and 48 % for the control and tested cells respectively, this increased to >98% in the 6-week LTCs initiated with cells that were overexpressing NUP98-HOXA10HD but remained constant at 39% in the control LTCs - suggesting a significant growth advantage conferred by the NUP98A10HD transgene. Importantly, RT-PCR genotyping of the colonies in these assays showed the majority of LTC-IC-derived CFCs from the NUP98-HOXA10HD-transduced cells to be BCR-ABL+, indicative of an even greater output of CFCs by the NUP98-HOXA10HD transduced BCR-ABL+ vs normal cells. These results highlight the potential of NUP98-HOXA10HD to selectively expand primitive CML cells isolated directly from chronic phase patients which will facilitate their further investigation and use to screen and validate new therapeutic agents.

scholarly journals Identification of Fc epsilon RIneg mast cells in mouse bone marrow cell cultures. Use of a monoclonal anti-p161 antibody.

1995 ◽  
Vol 182 (2) ◽  
pp. 575-579 ◽  
Author(s):  
C A Kinzer ◽  
A D Keegan ◽  
W E Paul
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Bone Marrow Cells ◽  
Marrow Cell ◽  
Surface Glycoprotein ◽  
Mouse Bone Marrow ◽  
Short Term ◽  
Mouse Bone Marrow Cell ◽  
Cell Surface Glycoprotein

A monoclonal hamster antibody (K-1) specific for a 161-kD mast cell surface glycoprotein was derived. p161 is expressed on normal and cultured mast cells and on some macrophages, but not on basophils or other hematopoietic cells. A population of Fc epsilon Rneg cells expressing p161 was found in short term cultures of bone marrow cells grown in interleukin (IL)-3. These cells were purified and propagated for extended periods in IL-3. They express c-kit and Fc gamma RII/III, contain alcian blue-positive granules and histamine, and secrete IL-3 in response to ionomycin treatment. Their morphology is consistent with that of mast cells. We propose that they represent Fc epsilon RIneg mast cells that can be detected and purified because of their p161 expression.

scholarly journals Distribution of mast-cell precursors in hematopoeitic and lymphopoietic tissues of mice.

1979 ◽  
Vol 150 (3) ◽  
pp. 482-490 ◽  
Author(s):  
Y Kitamura ◽  
M Shimada ◽  
S Go ◽  
H Matsuda ◽  
K Hatanaka ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Bone Marrow Cells ◽  
Cell Number ◽  
Precursor Cells ◽  
Lymphoid Cells ◽  
Experimental Systems ◽  
Chediak Higashi Syndrome

Two experimental systems were used to investigate the origin of precursor cells which differentiate into tissue mast cells in vivo. (a) Increase of mast cell number was examined in the skin, stomach, cecum, and mesentery of genetically mast cell-depleted WBB6F1 (WB X C57BL/6)-W/WV mice after the injection of various hematolymphoid cells of congenic +/+ mice. (b) Appearance of mast cells with giant granules was studied in irradiated C57BL/6-+/+ mice after the injection of lymphoid cells of C57BL/6-bgJ/bgJ (beige, Chediak-Higashi syndrome) mice. Concentrations of mast cell precursors in the thymus, lymph node and Peyer's patch were less than 0.1% of the concentration in the bone marrow. Neither treatment of donor bone marrow cells with anti-Thy-1.2 serum and complement nor thymectomy of the recipient mice affects the development of mast cells in the skin, stomach, cecum, and mesentery. Moreover, the number of mast cells increased to normal level when the skin of WBB6F1-W/WV mice was grafted on the back of nude athymic (BALB/c-nu/nu) mice. These results indicate that mast cell precursors are derived from hematopoietic tissues rather than lymphopoetic ones and that the differentiation of the precursor cells does not depend on T lymphocytes or the thymus.

scholarly journals Normal cycling patterns of hematopoietic stem cell subpopulations: an assay using long-term in vivo BrdU infusion

Blood ◽  
1985 ◽  
Vol 66 (6) ◽  
pp. 1460-1462 ◽  
Author(s):  
ME Pietrzyk ◽  
GV Priestley ◽  
NS Wolf
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Improved Method ◽  
Hematopoietic Stem ◽  
Infusion Study ◽  
A Cell ◽  
Cell Subpopulations ◽  
Over Time

It was found in a long-term bromodeoxyuridine (BrdU) infusion study that two or more different subpopulations of bone marrow stem cells exist in mice. One of these subpopulations appears to be noncycling and forms approximately 10% of eight-day CFU-S. Another one, a subpopulation of slowly cycling bone marrow cells, is represented as 14- day CFU-S. The 14-day CFU-S have a regular increment in the percentage of the subpopulation entering the cycle over time, with a cell generation half-time of 21 days. The cycling status in these experiments was ascertained by in vivo continuous long-term BrdU infusion. An improved method is presented for long-term BrdU infusion with UV killing of cycled cells.

Phenotypic correction of Fanconi anemia group C knockout mice

Blood ◽  
2000 ◽  
Vol 95 (2) ◽  
pp. 700-704 ◽  
Author(s):  
Kimberly A. Gush ◽  
Kai-Ling Fu ◽  
Markus Grompe ◽  
Christopher E. Walsh
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Mitomycin C ◽  
Fanconi Anemia ◽  
Bone Marrow Cells ◽  
Bone Marrow Failure ◽  
Genetic Disorder ◽  
Hematopoietic Stem ◽  
Marrow Cells

Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure, congenital anomalies, and a predisposition to malignancy. FA cells demonstrate hypersensitivity to DNA cross-linking agents, such as mitomycin C (MMC). Mice with a targeted disruption of the FANCC gene (fancc −/− nullizygous mice) exhibit many of the characteristic features of FA and provide a valuable tool for testing novel therapeutic strategies. We have exploited the inherent hypersensitivity offancc −/− hematopoietic cells to assay for phenotypic correction following transfer of the FANCC complementary DNA (cDNA) into bone marrow cells. Murine fancc −/− bone marrow cells were transduced with the use of retrovirus carrying the humanfancc cDNA and injected into lethally irradiated recipients. Mitomycin C (MMC) dosing, known to induce pancytopenia, was used to challenge the transplanted animals. Phenotypic correction was determined by assessment of peripheral blood counts. Mice that received cells transduced with virus carrying the wild-type gene maintained normal blood counts following MMC administration. All nullizygous control animals receiving MMC exhibited pancytopenia shortly before death. Clonogenic assay and polymerase chain reaction analysis confirmed gene transfer of progenitor cells. These results indicate that selective pressure promotes in vivo enrichment offancc-transduced hematopoietic stem/progenitor cells. In addition, MMC resistance coupled with detection of the transgene in secondary recipients suggests transduction and phenotypic correction of long-term repopulating stem cells.

scholarly journals Changes in numbers and types of mast cell colony-forming cells in the peritoneal cavity of mice after injection of distilled water: evidence that mast cells suppress differentiation of bone marrow-derived precursors

Blood ◽  
1988 ◽  
Vol 71 (3) ◽  
pp. 573-580 ◽  
Author(s):  
Y Kanakura ◽  
A Kuriu ◽  
N Waki ◽  
T Nakano ◽  
H Asai ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Peritoneal Cavity ◽  
Bone Marrow Cells ◽  
Water Injection ◽  
Lymphoid Cells ◽  
Distilled Water ◽  
Peritoneal Mast Cells ◽  
Chediak Higashi Syndrome

Abstract Two different types of cells in the peritoneal cavity of mice produce mast cell colonies in methylcellulose. “Large” mast cell colonies are produced by bone marrow-derived precursors resembling lymphoid cells by light microscopy (L-CFU-Mast), whereas “medium” and “small” mast cell colonies are produced by morphologically identifiable mast cells (M-CFU- Mast and S-CFU-Mast, respectively). In the present study we eradicated peritoneal mast cells by intraperitoneal (IP) injection of distilled water. The regeneration process was investigated to clarify the relationship between L-CFU-Mast, M-CFU-Mast, and S-CFU-Mast. After injection of distilled water, M-CFU-Mast and S-CFU-Mast disappeared, but L-CFU-Mast increased, and then M-CFU-Mast and S-CFU-Mast appeared, suggesting the presence of a hierarchic relationship. When purified peritoneal mast cells were injected two days after the water injection, the L-CFU-Mast did not increase. In the peritoneal cavity of WBB6F1-+/+ mice that had been lethally irradiated and rescued by bone marrow cells of C57BL/6-bgJ/bgJ (beige, Chediak-Higashi syndrome) mice, L-CFU-Mast were of bgJ/bgJ type, but M-CFU-Mast and S-CFU-Mast were of +/+ type. The injection of distilled water to the radiation chimeras resulted in the development of bgJ/bgJ-type M-CFU-Mast and then S-CFU-Mast. The presence of mast cells appeared to suppress the recruitment of L-CFU- Mast from the bloodstream and to inhibit the differentiation of L-CFU- Mast to M-CFU-Mast.

Development of both human connective tissue-type and mucosal-type mast cells in mice from hematopoietic stem cells with identical distribution pattern to human body

Blood ◽  
2004 ◽  
Vol 103 (3) ◽  
pp. 860-867 ◽  
Author(s):  
Naotomo Kambe ◽  
Hidefumi Hiramatsu ◽  
Mika Shimonaka ◽  
Hisanori Fujino ◽  
Ryuta Nishikomori ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mast Cell ◽  
Mast Cells ◽  
Hematopoietic Stem Cells ◽  
Cell Development ◽  
Tissue Type ◽  
Human Mast Cell ◽  
Hematopoietic Stem ◽  
Nog Mice

Abstract The transplantation of primitive human cells into sublethally irradiated immune-deficient mice is the well-established in vivo system for the investigation of human hematopoietic stem cell function. Although mast cells are the progeny of hematopoietic stem cells, human mast cell development in mice that underwent human hematopoietic stem cell transplantation has not been reported. Here we report on human mast cell development after xenotransplantation of human hematopoietic stem cells into nonobese diabetic severe combined immunodeficient \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \((\mathrm{NOD{/}SCID}){/}{\gamma}_{\mathrm{c}}^{null}\) \end{document} (NOG) mice with severe combined immunodeficiency and interleukin 2 (IL-2) receptor γ-chain allelic mutation. Supported by the murine environment, human mast cell clusters developed in mouse dermis, but they required more time than other forms of human cell reconstitution. In lung and gastric tract, mucosal-type mast cells containing tryptase but lacking chymase located on gastric mucosa and in alveoli, whereas connective tissue-type mast cells containing both tryptase and chymase located on gastric submucosa and around major airways, as in the human body. Mast cell development was also observed in lymph nodes, spleen, and peritoneal cavity but not in the peripheral blood. Xenotransplantation of human hematopoietic stem cells into NOG mice can be expected to result in a highly effective model for the investigation of human mast cell development and function in vivo.

scholarly journals Rescue of W-associated mast cell defects in W/Wv bone marrow cells by ectopic expression of normal and mutant epidermal growth factor receptors

Blood ◽  
1993 ◽  
Vol 82 (5) ◽  
pp. 1463-1470
Author(s):  
T von Ruden ◽  
L Stingl ◽  
A Ullrich ◽  
EF Wagner
Keyword(s):  
Signal Transduction ◽  
Bone Marrow ◽  
Mast Cell ◽  
Growth Factor ◽  
Mast Cells ◽  
Epidermal Growth Factor ◽  
Bone Marrow Cells ◽  
Ectopic Expression ◽  
Tissue Type ◽  
Epidermal Growth

Abstract The normal human epidermal growth factor receptor (EGF-R) (HERc), a chimeric EGF-R/v-erbB (HERerbB) receptor, and the ligand-independent oncogenic EGF-R variant (v-erbB) were used to correct the mast cell defects in W/Wv bone marrow (BM) cells. In culture, all three receptor molecules transduced functional mitogenic signals in infected interleukin-3 (IL-3)-dependent bone marrow-derived mast cells (BMMCs) and enabled their differentiation into safranin-positive mast cells resembling connective tissue-type mast cells (CTMCs). Furthermore, expression of these receptors restored the capacity of W/Wv BMMCs to colonize the peritoneal cavity of mast cell-deficient W/Wv mice where they differentiated to safranin-positive cells with similar frequencies as wild-type BMMCs. These experiments show that expression of normal and mutant EGF-Rs in W/Wv BM cells is able to complement the function of the c-kit-encoded Steel factor receptor (SLF-R) in mast cell development. We conclude that signal transduction by normal and mutant EGF-Rs in murine hematopoietic cells apparently involves components also used by the SLF-R, which suggests that these receptors use overlapping pathways for signal transduction.

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