Bone Marrow Adipocytes: A Critical Player in the Bone Marrow Microenvironment

Recognized for nearly 100 years, bone marrow adipocytes (BMAs) form bone marrow niches that contain hematopoietic and bone cells, the roles of which have long been underestimated. Distinct from canonical white, brown, and beige adipocytes, BMAs derived from bone marrow mesenchymal stromal cells possess unique characteristics and functions. Recent single-cell sequencing studies have revealed the differentiation pathway, and seminal works support the tenet that BMAs are critical regulators in hematopoiesis, osteogenesis, and osteoclastogenesis. In this review, we discuss the origin and differentiation of BMAs, as well as the roles of BMAs in hematopoiesis, osteogenesis, osteoclastogenesis, and immune regulation. Overall, BMAs represent a novel target for bone marrow-related diseases, including osteoporosis and leukemia.

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The New Role of CD163 in the Differentiation of Bone Marrow Stromal Cells into Vascular Endothelial-Like Cells

Stem Cells International ◽

10.1155/2016/2539781 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Wei Lu ◽

Le Su ◽

Zhezheng Yu ◽

Shangli Zhang ◽

Junying Miao

Keyword(s):

Bone Marrow ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Vascular Endothelial Cells ◽

Signal Pathway ◽

Marrow Stromal Cells ◽

Vascular Endothelial ◽

Cd163 Expression ◽

Important Solution ◽

Novel Target

Bone marrow stromal cells (BMSCs) can differentiate into vascular endothelial cells (VECs). It is regarded as an important solution to cure many diseases, such as ischemic diseases and diabetes. However, the mechanisms underlying BMSC differentiation into VECs are not well understood. Recent reports showed that CD163 expression was associated with angiogenesis. In this study, overexpression of CD163 in BMSCs elevated the protein level of the endothelial-associated markers CD31, Flk-1, eNOS, and VE-cadherin, significantly increased the proportion of Alexa Fluor 488-acetylated-LDL-positive VECs, and promoted angiogenesis on Matrigel. Furthermore, we demonstrated that CD163 acted downstream homeobox containing 1 (Hmbox1) and upstream fibroblast growth factor 2 (FGF-2). These data suggested that CD163 was involved in Hmbox1/CD163/FGF-2 signal pathway in BMSC differentiation into vascular endothelial-like cells. We found a new signal pathway and a novel target for further investigating the gene control of BMSC differentiation into a VEC lineage.

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The Atypical Gtpase Rhou Lies Downstream IL6/STAT3 and Regulates Myeloma Plasma Cells Adhesion/Motility

Blood ◽

10.1182/blood.v128.22.5661.5661 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5661-5661

Author(s):

Sara Nunes Canovas ◽

Marilena Carrino ◽

Sabrina Manni ◽

Laura Quotti Tubi ◽

Martina Manzoni ◽

...

Keyword(s):

Bone Marrow ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Poor Prognosis ◽

Rho Gtpase ◽

Conflicts Of Interest ◽

Fold Change ◽

Marrow Stromal Cells ◽

Genetic Abnormalities ◽

Bone Marrow Niches

Abstract RhoU is an atypical G protein of the Rho GTPase family endowed with a very high intrinsic guanine nucleotide exchange activity ensuring a prevalent GTP-loaded conformation. It is present at very low levels in most cells, however some reports have shown that the Wnt-1 and STAT3 pathways might regulate its expression which resulted highly increased in malignant tumors. Since the IL6R/STAT3 signaling is of critical in Multiple Myeloma (MM) growth, homing and adhesion to marrow stroma and RhoU GTPase may mediate the induction of filopodia formation and stress fiber dissolution, we aimed at studying the role of this protein in MM malignancy. mRNA expression studies unraveled that MM patients have heterogeneous levels of RhoU ranging from -0.7 fold change to 18.5 fold change when normalized over controls. By analyzing available gene expression data sets, we found that RhoU expression changes were associated with distinctive expression of 557 genes. We also found a correlation between RhoU levels and genetic abnormalities that associate with a poor prognosis in MM patients, namely the t(4;14), del(13) and 1q gain. RhoU was positively modulated by IL-6 and by soluble factors from bone marrow stromal cells' culture. Its expression was down-modulated after STAT3 inhibition with the chemical inhibitor Stattic, even in the presence of IL-6. The treatment with Stattic also decreased MM cells' migration capability. Remarkably, RhoU knock down by siRNA caused changes in MM cells' phenotype and deranged adhesion/migration functional properties. Lastly we have looked into changes in RhoU expression after the treatment of MM cells with Lenalidomide, known to act on MM microenvironment and alter MM cells' adhesion to protective bone marrow niches. Surprisingly, treatment of MM cell lines or from patients with Lenalidomide led to an upregulation of RhoU expression in the cells before onset of apoptosis after 72 hours. Our data point to a functional role in cell adhesion, migration and shape for RhoU GTPase in a subset of MM, in particular in cases with genetic abnormalities correlating with a poor prognosis. RhoU is downstream from STAT3/IL-6 and likely from growth factor delivered by bone marrow stromal cells. The upregulation of RhoU expression after treatment with Lenalidomide was associated to a stall of the cellular cytoskeleton and subsequent apoptosis. Thus RhoU might be important in MM pathogenesis and could become a suitable target to disrupt the MM plasma cell interaction with protective bone marrow niches. Disclosures No relevant conflicts of interest to declare.

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MicroRNA-141-3p Negatively Modulates SDF-1 Expression in Age-Dependent Pathophysiology of Human and Murine Bone Marrow Stromal Cells

The Journals of Gerontology Series A ◽

10.1093/gerona/gly186 ◽

2018 ◽

Vol 74 (9) ◽

pp. 1368-1374 ◽

Cited By ~ 9

Author(s):

Sudharsan Periyasamy-Thandavan ◽

John Burke ◽

Bharati Mendhe ◽

Galina Kondrikova ◽

Ravindra Kolhe ◽

...

Keyword(s):

Bone Marrow ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Bone Cells ◽

Marrow Stromal Cells ◽

Luciferase Reporter ◽

Bm Niche ◽

Human Bmscs ◽

Age Dependent ◽

The Impact

Abstract Stromal cell-derived factor-1 (SDF-1 or CXCL12) is a cytokine secreted by cells including bone marrow stromal cells (BMSCs). SDF-1 plays a vital role in BMSC migration, survival, and differentiation. Our group previously reported the role of SDF-1 in osteogenic differentiation in vitro and bone formation in vivo; however, our understanding of the post-transcriptional regulatory mechanism of SDF-1 remains poor. MicroRNAs are small noncoding RNAs that post-transcriptionally regulate the messenger RNAs (mRNAs) of protein-coding genes. In this study, we aimed to investigate the impact of miR-141-3p on SDF-1 expression in BMSCs and its importance in the aging bone marrow (BM) microenvironment. Our data demonstrated that murine and human BMSCs expressed miR-141-3p that repressed SDF-1 gene expression at the functional level (luciferase reporter assay) by targeting the 3′-untranslated region of mRNA. We also found that transfection of miR-141-3p decreased osteogenic markers in human BMSCs. Our results demonstrate that miR-141-3p expression increases with age, while SDF-1 decreases in both the human and mouse BM niche. Taken together, these results support that miR-141-3p is a novel regulator of SDF-1 in bone cells and plays an important role in the age-dependent pathophysiology of murine and human BM niche.

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Expansion induced microRNA changes in bone marrow mesenchymal stromal cells reveals interplay between immune regulation and cell cycle

Aging ◽

10.18632/aging.101088 ◽

2016 ◽

Vol 8 (11) ◽

pp. 2799-2813 ◽

Cited By ~ 11

Author(s):

Lotta Kilpinen ◽

Amarjit Parmar ◽

Dario Greco ◽

Matti Korhonen ◽

Petri Lehenkari ◽

...

Keyword(s):

Cell Cycle ◽

Bone Marrow ◽

Mesenchymal Stromal Cells ◽

Immune Regulation ◽

Stromal Cells

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Periostin Mediates Oestrogen-Induced Osteogenic Differentiation of Bone Marrow Stromal Cells in Ovariectomised Rats

BioMed Research International ◽

10.1155/2020/9405909 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Chunrong Li ◽

Xin Li ◽

Xian Wang ◽

Pei Miao ◽

Jia Liu ◽

...

Keyword(s):

Bone Marrow ◽

Bone Formation ◽

Osteogenic Differentiation ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Marrow Stromal Cells ◽

Ovx Rats ◽

Novel Target

Osteoporosis is a metabolic disease that results in the progressive loss of bone mass, which, in postmenopausal women, is related to oestrogen deficiency. Periostin (POSTN) plays a key role in the early stages of bone formation. However, whether POSTN participates in oestradiol regulation of osteogenic differentiation of bone marrow stromal cells (BMSCs) from ovariectomised (OVX) rats remains unclear. In vivo, using microcomputed tomography (micro-CT), immunohistochemistry, and dynamic analysis of femurs, we found that 17β-E2 promotes bone formation and POSTN expression at the endosteal surface. In vitro, 17β-E2 upregulated POSTN expression in OVX-BMSCs. POSTN overexpression activated the Wnt/β-catenin signalling pathway and enhanced osteogenic differentiation of OVX-BMSCs. Furthermore, knockdown of Postn blocks the involvement of 17β-E2 in the osteogenic differentiation of OVX-BMSCs. Collectively, our study indicated the role of POSTN in the osteogenesis and stemness of OVX-BMSCs and proves that 17β-E2 reduces osteoporosis and promotes osteogenesis through the POSTN-Wnt/β-catenin pathway. POSTN could, therefore, be a novel target gene for anti-osteoporosis therapies.

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Surgical vacuum filter-derived stromal cells are superior in proliferation to human bone marrow aspirate

Stem Cell Research & Therapy ◽

10.1186/s13287-019-1461-0 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 2

Author(s):

Katharina Henze ◽

Monika Herten ◽

Marcel Haversath ◽

André Busch ◽

Sven Brandau ◽

...

Keyword(s):

Bone Marrow ◽

Cancellous Bone ◽

Stromal Cells ◽

Mononuclear Cells ◽

Bone Cells ◽

Vacuum Filter ◽

Vacuum Suction ◽

Colony Forming Units ◽

High Concentrations

Abstract Background During joint replacement, surgical vacuum suction guarantees a sufficient overview on the situs. We assume high concentrations of mesenchymal stromal cells (MSCs) on surgical vacuum filters. We compared the in vitro proliferative and differentiation potency of cells from the following: (i) bone marrow (BM), (ii) cancellous bone (CB), (iii) vacuum filter (VF), and (iv) cell saver filtrate reservoir (SF) in 32 patients undergoing elective total hip replacement. Methods Mononuclear cells (MNC) were isolated, and cell proliferation and colony-forming units (CFU) were measured. Adherent cells were characterized by flow cytometry for MSC surface markers. Cells were incubated with osteogenic, adipogenic, and chondrogenic stimuli. Cells were cytochemically stained and osteoblastic expression (RUNX-2, ALP, and BMP-2) investigated via qPCR. Results Dependent on the source, initial MNC amount as well as CFU number was significantly different whereas generation time did not vary significantly. CFU numbers from VF were superior to those from SR, BM, and CB. The resulting amount of MSC from the respective source was highest in the vacuum filter followed by reservoir, aspirate, and cancellous bone. Cells from all groups could be differentiated into the three mesenchymal lines demonstrating their stemness nature. However, gene expression of osteoblastic markers did not differ significantly between the groups. Conclusion We conclude that surgical vacuum filters are able to concentrate tissue with relevant amounts of MSCs. A new potent source of autologous regeneration material with clinical significance is identified. Further clinical studies have to elucidate the regenerative potential of this material in an autologous setting.

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