bone marrow microenvironment
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2022 ◽  
Vol 146 ◽  
pp. 112548
Author(s):  
Xiaoya Zhou ◽  
Li Huang ◽  
Jieying Wu ◽  
Yuhua Qu ◽  
Hua Jiang ◽  
...  

Author(s):  
Ruolan You ◽  
Diyu Hou ◽  
Bin Wang ◽  
Jingru Liu ◽  
Xiaoting Wang ◽  
...  

2021 ◽  
pp. 135245852110606
Author(s):  
Pamela Sarkar ◽  
Juliana Redondo ◽  
Kelly Hares ◽  
Steven Bailey ◽  
Anastasia Georgievskaya ◽  
...  

Background: Cell-based therapies for multiple sclerosis (MS), including those employing autologous bone marrow-derived mesenchymal stromal cells (MSC) are being examined in clinical trials. However, recent studies have identified abnormalities in the MS bone marrow microenvironment. Objective: We aimed to compare the secretome of MSC isolated from control subjects (C-MSC) and people with MS (MS-MSC) and explore the functional relevance of findings. Methods: We employed high throughput proteomic analysis, enzyme-linked immunosorbent assays and immunoblotting, as well as in vitro assays of enzyme activity and neuroprotection. Results: We demonstrated that, in progressive MS, the MSC secretome has lower levels of mitochondrial fumarate hydratase (mFH). Exogenous mFH restores the in vitro neuroprotective potential of MS-MSC. Furthermore, MS-MSC expresses reduced levels of fumarate hydratase (FH) with downstream reduction in expression of master regulators of oxidative stress. Conclusions: Our findings are further evidence of dysregulation of the bone marrow microenvironment in progressive MS with respect to anti-oxidative capacity and immunoregulatory potential. Given the clinical utility of the fumaric acid ester dimethyl fumarate in relapsing–remitting MS, our findings have potential implication for understanding MS pathophysiology and personalised therapeutic intervention.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Joschka Heil ◽  
Victor Olsavszky ◽  
Katrin Busch ◽  
Kay Klapproth ◽  
Carolina de la Torre ◽  
...  

AbstractWithin the bone marrow microenvironment, endothelial cells (EC) exert important functions. Arterial EC support hematopoiesis while H-type capillaries induce bone formation. Here, we show that BM sinusoidal EC (BM-SEC) actively control erythropoiesis. Mice with stabilized β-catenin in BM-SEC (Ctnnb1OE-SEC) generated by using a BM-SEC-restricted Cre mouse line (Stab2-iCreF3) develop fatal anemia. While activation of Wnt-signaling in BM-SEC causes an increase in erythroblast subsets (PII–PIV), mature erythroid cells (PV) are reduced indicating impairment of terminal erythroid differentiation/reticulocyte maturation. Transplantation of Ctnnb1OE-SEC hematopoietic stem cells into wildtype recipients confirms lethal anemia to be caused by cell-extrinsic, endothelial-mediated effects. Ctnnb1OE-SEC BM-SEC reveal aberrant sinusoidal differentiation with altered EC gene expression and perisinusoidal ECM deposition and angiocrine dysregulation with de novo endothelial expression of FGF23 and DKK2, elevated in anemia and involved in vascular stabilization, respectively. Our study demonstrates that BM-SEC play an important role in the bone marrow microenvironment in health and disease.


Author(s):  
Débora Bifano Pimenta ◽  
Vanessa Araujo Varela ◽  
Tarcila Santos Datoguia ◽  
Victória Bulcão Caraciolo ◽  
Gabriel Herculano Lopes ◽  
...  

Bone marrow (BM) is a highly complex tissue that provides important regulatory signals to orchestrate hematopoiesis. Resident and transient cells occupy and interact with some well characterized niches to produce molecular and cellular mechanisms that interfere with differentiation, migration, survival, and proliferation in this microenvironment. The acute myeloid leukemia (AML), the most common and severe hematological neoplasm in adults, arises and develop in the BM. The osteoblastic, vascular, and reticular niches provide surface co-receptors, soluble factors, cytokines, and chemokines that mediate important functions on hematopoietic cells and leukemic blasts. There are some evidences of how AML modify the architecture and function of these three BM niches, but it has been still unclear how essential those modifications are to maintain AML development. Basic studies and clinical trials have been suggesting that disturbing specific cells and molecules into the BM niches might be able to impair leukemia competencies. Either through niche-specific molecule inhibition alone or in combination with more traditional drugs, the bone marrow microenvironment is currently considered the potential target for new strategies to treat AML patients. This review describes the cellular and molecular constitution of the BM niches under healthy and AML conditions, presenting this anatomical compartment by a new perspective: as a prospective target for current and next generation therapies.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 892-892
Author(s):  
Lingling Shu ◽  
Jinyuan Li ◽  
Shuzhao Chen ◽  
Han-Ying Huang ◽  
Yang Li ◽  
...  

Abstract Multiple myeloma (MM) often occurs in middle-aged, elderly and obese patients with ectopic accumulation of fat cells in the bone marrow. Bone marrow adipocytes (BMAs) display unique immunomodulatory properties instead of simply providing energy substrates, which can cause distinct change of bone marrow microenvironment. Although BMA accounts for 70% of the total volume of bone marrow, the mechanism on how BMA affects tumor progression remains elusive. This study aims to explore the pathogenesis of BMA in promoting myeloma and new potential treatment strategies targeting bone marrow microenvironment. Newly diagnosed MM patients in our cancer center and their relative healthy controls are recruited. A significant increase of BMA quantity in multiple myeloma patients was observed. Moreover, analysis of transcriptome sequencing data of BMA derived from MM patients demonstrated a distinctive gene expression profiles (Fig A). It worth to note that, expression of fatty acid-binding protein 4 (FABP4, also known as A-FABP or aP2), a member of the FABP family abundantly expressed in adipocytes, functions as a lipid-binding chaperone that regulates trafficking and cellular signaling of fatty acids, and plays an important role in linking lipid metabolism with immunity and inflammation, was increased significantly in BMA of MM patients (Fig B). To further explore the role of FABP4 in pathogenesis in MM, FABP4 knockout (KO) mice and their wide-type (WT) littermates were adopted, and fed with standard chow (STC) or high-fat diet (HFD, 45 kcal % Fat, D12451). FABP4 deficiency significantly attenuated the tumor burden and MM-related osteolytic lesions in mice fed with HFD (Fig C-D). Moreover, levels of pro-inflammatory cytokines including TNFα, IL-6, RANKL and DPP4 were significantly reduced in FABP4 deficient adipocytes (Fig E). Flow cytometry analysis showed that the infiltration and pro-inflammatory polarization (M1/M2) of macrophages (MΦ) decreased significantly in FABP4 KO bone marrow (Fig F). In addition, FABP4 promoted the infiltration of Th1 and Th17 cells, while impaired the recruitment of Th2 and Treg cells (Fig G). Furthermore, administration of exogenous FABP4 recombinant protein significantly increased the fatty acid uptake and oxygen consumption of myeloma cells (Fig H). In contrast, pharmacological inhibition of FABP4 with BMS309403 alleviated the invasion and metastasis of MM in mice fed with HFD (Fig I-J). In summary, BMA increased in MM patients, reshapes the metabolism and immunity in bone marrow microenvironment through regulating FABP4 functions. FABP4 enhanced the energy and lipid metabolism of myeloma cells, and manipulated the bone marrow microenvironment to pro-tumor environment, therefore promoted the proliferation and migration of myeloma cells. This study will not only clarify the critical role of BMA in MM pathogenesis, but also provide therapeutic potential of FABP4 selective inhibitor BMS309403 for multiple myeloma treatment, especially for obese MM patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.


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