scholarly journals GM-CSF impairs erythropoiesis by disrupting erythroblastic island formation via macrophages

2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Weijie Cao ◽  
Wenjuan Fan ◽  
Fang Wang ◽  
Yinyin Zhang ◽  
Guanghua Wu ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Inflammatory Diseases ◽  
Mouse Bone Marrow ◽  
Adhesion Molecule Expression ◽  
Supporting Function ◽  
Gm Csf ◽  
Erythroblastic Island ◽  
Novel Strategy

AbstractAnemia is a significant complication of chronic inflammation and may be related to dysregulated activities among erythroblastic island (EBI) macrophages. GM-CSF was reported to be upregulated and attracted as a therapeutic target in many inflammatory diseases. Among EBIs, we found that the GM-CSF receptor is preferentially and highly expressed among EBI macrophages but not among erythroblasts. GM-CSF treatment significantly decreases human EBI formation in vitro by decreasing the adhesion molecule expression of CD163. RNA-sequence analysis suggests that GM-CSF treatment impairs the supporting function of human EBI macrophages during erythropoiesis. GM-CSF treatment also polarizes human EBI macrophages from M2-like type to M1-like type. In addition, GM-CSF decreases mouse bone marrow (BM) erythroblasts as well as EBI macrophages, leading to a reduction in EBI numbers. In defining the molecular mechanism at work, we found that GM-CSF treatment significantly decreases the adhesion molecule expression of CD163 and Vcam1 in vivo. Importantly, GM-CSF treatment also decreases the phagocytosis rate of EBI macrophages in mouse BM as well as decreases the expression of the engulfment-related molecules Mertk, Axl, and Timd4. In addition, GM-CSF treatment polarizes mouse BM EBI macrophages from M2-like type to M1-like type. Thus, we document that GM-CSF impairs EBI formation in mice and humans. Our findings support that targeting GM-CSF or reprogramming EBI macrophages might be a novel strategy to treat anemia resulting from inflammatory diseases.

scholarly journals GM-CSF Impairs Erythropoiesis by Disrupting Erythroblastic Island Formation via Macrophages

2021 ◽  
Author(s):  
Weijie Cao ◽  
Wenjuan Fan ◽  
Fang Wang ◽  
Yinyin Zhang ◽  
Guanghua Wu ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Inflammatory Diseases ◽  
Mouse Bone Marrow ◽  
Adhesion Molecule Expression ◽  
Supporting Function ◽  
Gm Csf ◽  
Erythroblastic Island ◽  
Novel Strategy

Abstract Anemia is a significant complication of chronic inflammation and may be related to dysregulated activities among erythroblastic island (EBI) macrophages. GM-CSF was reported to be upregulated and attracted as a therapeutic target in many inflammatory diseases. Among EBIs, we found that the GM-CSF receptor is preferentially and highly expressed among EBI macrophages but not among erythroblasts. GM-CSF treatment significantly decreases human EBI formation in vitro by decreasing the adhesion molecule expression of CD163. RNA-sequence analysis suggests that GM-CSF treatment impairs the supporting function of human EBI macrophages during erythropoiesis. GM-CSF treatment also polarizes human EBI macrophages from M2-like type to M1-like type. In addition, GM-CSF decreases mouse bone marrow (BM) erythroblasts as well as EBI macrophages, leading to a reduction in EBI numbers. In defining the molecular mechanism at work, we found that GM-CSF treatment significantly decreases the adhesion molecule expression of CD163 and Vcam1 in vivo. Importantly, GM-CSF treatment also decreases the phagocytosis rate of EBI macrophages in mouse BM as well as decreases the expression of the engulfment-related molecules Mertk, Axl, and Timd4. In addition, GM-CSF treatment polarizes mouse BM EBI macrophages from M2-like type to M1-like type. Thus, we document that GM-CSF impairs EBI formation in mice and humans. Our findings support that targeting GM-CSF or reprogramming EBI macrophages might be a novel strategy to treat anemia resulting from inflammatory diseases.

scholarly journals Ocular penetration of fluorometholone-loaded PEG-PLGA nanoparticles functionalized with cell-penetrating peptides

Nanomedicine ◽  
2019 ◽  
Vol 14 (23) ◽  
pp. 3089-3104 ◽  
Author(s):  
Roberto Gonzalez-Pizarro ◽  
Graziella Parrotta ◽  
Rodrigo Vera ◽  
Elena Sánchez-López ◽  
Ruth Galindo ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Physicochemical Characteristics ◽  
Plga Nanoparticles ◽  
Cell Penetrating Peptides ◽  
In Vivo Models ◽  
Corneal Epithelial ◽  
Cell Penetrating ◽  
Novel Strategy

Aim: Development of fluorometholone-loaded PEG-PLGA nanoparticles (NPs) functionalized with cell-penetrating peptides (CPPs) for the treatment of ocular inflammatory disorders. Materials & methods: Synthesized polymers and peptides were used for elaboration of functionalized NPs, which were characterized physicochemically. Cytotoxicity and ability to modulate the expression of proinflammatory cytokines were evaluated in vitro using human corneal epithelial cells (HCE-2). NPs uptake was assayed in both in vitro and in vivo models. Results: NPs showed physicochemical characteristics suitable for ocular administration without evidence of cytotoxicity. TAT-NPs and G2-NPs were internalized and displayed anti-inflammatory activity in both HCE-2 cells and mouse eye. Conclusion: TAT-NPs and G2-NPs could be considered a novel strategy for the treatment of ocular inflammatory diseases of the anterior and posterior segment.

Primitive interleukin 3 null hematopoietic cells transduced with BCR-ABL show accelerated loss after culture of factor-independence in vitro and leukemogenic activity in vivo

Blood ◽  
2002 ◽  
Vol 100 (10) ◽  
pp. 3731-3740 ◽  
Author(s):  
Xiaoyan Jiang ◽  
Eddy Ng ◽  
Calvin Yip ◽  
Wolfgang Eisterer ◽  
Yves Chalandon ◽  
...  
Keyword(s):  
Mast Cells ◽  
Hematopoietic Cells ◽  
Production Factor ◽  
Mouse Bone Marrow ◽  
Paracrine Effects ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Large Populations

Primitive chronic myeloid leukemia cells display a unique autocrine interleukin 3 (IL-3)/granulocyte–colony-stimluating factor (G-CSF) mechanism that may explain their abnormal proliferation and differentiation control. Here we show that BCR-ABL transduction of primitive Sca-1+ lin− mouse bone marrow (BM) cells causes immediate activation of IL-3, G-CSF, and granulocyte macrophage–colony-stimulating factor (GM-CSF) expression in these cells. Their autocrine IL-3–mediated growth dependence is thus demonstrable only in clonal cultures where paracrine effects are reduced. Interestingly, upon continued culture, these cells produce large populations of rapidly proliferating mast cells in which only the IL-3 autocrine mechanism is consistently maintained, together with evidence of hyperphosphorylation of p210BCR-ABL and STAT5 and retention of a multilineage but attenuated in vivo leukemogenic potential characterized by a prolonged latency. BCR-ABL transduction of IL-3−/− Sca-1+ lin− BM cells initially activates GM-CSF and G-CSF production, factor independence, and the ability to generate phenotypically indistinguishable populations of mast cells. However, maintenance of factor independence, and p210BCR-ABL and STAT 5 activation beyond 4 to 6 weeks, requires rescue with an IL-3 transgene. The cultured BCR-ABL–transduced IL-3−/− cells also lack leukemogenic activity in vivo. These findings provide new evidence that IL-3 production is a rapid, sustained, and biologically relevant consequence of BCR-ABL expression in primitive hematopoietic cells with multilineage leukemogenic activity.

scholarly journals Isolation of High Purity Mouse Mesenchymal Stem Cells through Depleting Macrophages Using Liposomal Clodronate

2022 ◽  
Author(s):  
Ju Han Song ◽  
Jung-Woo Kim ◽  
Mi Nam Lee ◽  
Sin-Hye Oh ◽  
Xianyu Piao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
High Purity ◽  
Mouse Bone Marrow ◽  
Preclinical Studies ◽  
Liposomal Clodronate ◽  
Novel Strategy

Abstract BACKGROUND: The use of mouse bone marrow mesenchymal stem cells (mBMSCs) represents a promising strategy for performing preclinical studies in the field of cell-based regenerative medicine; however, mBMSCs obtained via conventional isolation methods have two drawbacks, i.e., (i) they are heterogeneous due to frequent macrophage contamination, and (ii) they require long-term culturing for expansion. METHODS: In the present study, we report a novel strategy to generate highly pure mBMSCs using liposomal clodronate. This approach is based on the properties of the two cell populations, i.e., BMSCs (to adhere to the plasticware in culture dishes) and macrophages (to phagocytose liposomes). RESULTS: Liposomal clodronate added during the first passage of whole bone marrow culture was selectively engulfed by macrophages in the heterogeneous cell population, resulting in their effective elimination without affecting the MSCs. This method allowed the generation of numerous high-purity Sca-1+CD44+F4/80− mBMSCs (> 95%) with just one passaging. Comparative studies with mBMSCs obtained using conventional methods revealed that the mBMSCs obtained in the present study had remarkably improved experimental utilities, as demonstrated by in vitro multilineage differentiation and in vivo ectopic bone formation assays. CONCLUSION: Our newly developed method, which enables the isolation of mBMSCs using simple and convenient protocol, will aid preclinical studies based on the use of MSCs.

Prospective Isolation of Human Eosinophil-Committed Progenitors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1285-1285
Author(s):  
Yasuo Mori ◽  
Hiromi Iwasaki ◽  
Goichi Yoshimoto ◽  
Aki Okeda ◽  
Toshihiro Miyamoto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mononuclear Cells ◽  
Inflammatory Diseases ◽  
Hypereosinophilic Syndrome ◽  
Mouse Bone Marrow ◽  
Hematopoietic Stem ◽  
Human Eosinophil ◽  
Murine Bone Marrow

Abstract Eosinophils play an important role in the pathogenesis of allergic reactions or chronic inflammatory diseases by releasing various types of cytokines and chemical mediators. Recently, we have identified murine eosinophil-committed progenitors (mEoPs) in mouse bone marrow. The expression of receptor for IL-5, a critical cytokine for proliferation and differentiation of eosinophils, was a key marker to isolate mEoPs: mEoP was IL-5Ra+Lineage(lin)-CD34+c-Kitlow population in murine bone marrow (J Exp Med.201, 1891ndash;7, 2005). Here we report that EoPs are prospectively isolatable also in human bone marrow. We analyzed the expression of human IL-5Ra in human stem and progenitor populations, and found that a fraction of common myeloid progenitor (CMP; lin-CD34+CD38+CD45RA-IL-3Ra+) population expressed hIL-5Ra on their surface by using anti-human IL-5Ra monoclonal antibodies. IL-5Ra protein and mRNA were undetectable in hematopoietic stem cells (HSCs; lin-CD34+CD38-), common lymphoid progenitors (CLPs; lin-CD34+CD38+CD10+), megakaryocyte/erythrocyte progenitors (MEPs; lin-CD34+CD38+CD45RA-IL-3Ra-), or granulocyte/monocyte progenitors(GMPs; lin-CD34+CD38+CD45RA+IL-3Ra+) by FACS and RT-PCR, respectively. The IL-5Ra+ cells within the CMP fraction constituted only ~0.04% of steady-state bone marrow mononuclear cells, and gave rise only to pure eosinophil colonies. Thus we termed this population as human EoP (hEoP). Both HSCs and the IL-5Ra- fraction of CMPs gave rise to IL-5Ra+ hEoPs in vitro in the presence of IL-3 and GM-CSF, while MEPs or GMPs never generated hEoPs, indicating that human eosinophil pathway diverges at the CMP stage, and that the eosinophil potential was lost at the GMP or MEP stage. Accordingly, the human eosinophil pathway is different from that in murine hematopoiesis where mEoPs develop from the GMP stage. Strikingly, the number of hEoPs in the bone marrow of patients with hypereosinophilic syndrome was significantly (~4-fold) increased as compared to that in normal bone marrow, suggesting that hEoP represents a critical stage for eosinophilia in vivo. Thus, the hEoP is an attractive candidate for therapeutic target in eosinophil-related allergic and inflammatory disorders. This population might also be very useful to study the molecular mechanism of human eosinophil development.

scholarly journals Bifidobacterium longum attenuates ovariectomy-induced bone loss via modulating the Immunoporotic Breg-Treg-Th17 cell axis

2022 ◽  
Author(s):  
Leena Sapra ◽  
Niti Shokeen ◽  
Konica Gupta ◽  
Chaman Saini ◽  
Asha Bhardwaj ◽  
...  
Keyword(s):  
Th17 Cell ◽  
Bone Marrow Cells ◽  
Inflammatory Diseases ◽  
Bifidobacterium Longum ◽  
Mouse Bone Marrow ◽  
Mice Model ◽  
Cell Axis ◽  
Immunomodulatory Potential

Discoveries in the last few years have emphasized the existence of an enormous breadth of communication between osteo-immune system. These discoveries fuel novel approaches for the treatment of several bone-pathologies including osteoporosis, an inflammatory bone anomaly affecting more than 500 million people globally. Bifidobacterium longum (BL) is preferred probiotic of choice due to its varied immunomodulatory potential in alleviating various inflammatory diseases. Here, we evaluate the effect of BL in ovariectomy (ovx)-induced post-menopausal osteoporotic mice model. Our in vitro findings reveal that BL suppresses the differentiation and functional activity of RANKL-induced osteoclastogenesis in both mouse bone marrow cells and human PBMCs. Our in vivo data clearly establish that BL exhibits osteoprotective potential via modulating the immunoporotic Breg-Treg-Th17 cell-axis. Furthermore, micro-CT and bone mechanical strength data support that BL supplementation significantly enhanced bone mass and strength, and improved microarchitecture in ovx mice. Remarkably, alteration in frequencies of CD19+CD1dhiCD5+ Bregs, CD4+Foxp3+IL-10+ Tregs, and CD4+Rorgt+IL-17+ Th17 immune cells in distinct lymphoid organs along with serum-cytokine data (enhanced anti-osteoclastogenic cytokines IFN-g; and IL-10 and reduced osteoclastogenic-cytokines IL-6, IL-17, and TNF-a) strongly support the immunomodulatory potential of BL. Altogether our findings establish a novel osteo-protective and immunoporotic potential of BL in augmenting bone health under osteoporotic conditions.

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