scholarly journals Roles of MicroRNAs in Osteogenesis or Adipogenesis Differentiation of Bone Marrow Stromal Progenitor Cells

2021 ◽  
Vol 22 (13) ◽  
pp. 7210
Author(s):  
Ya-Li Zhang ◽  
Liang Liu ◽  
Yaser Peymanfar ◽  
Paul Anderson ◽  
Cory J. Xian
Keyword(s):  
Bone Marrow ◽  
Bone Growth ◽  
Target Genes ◽  
Microrna Regulation ◽  
Growth Defects ◽  
Multipotent Cells ◽  
Underlying Mechanisms

Bone marrow stromal cells (BMSCs) are multipotent cells which can differentiate into chondrocytes, osteoblasts, and fat cells. Under pathological stress, reduced bone formation in favour of fat formation in the bone marrow has been observed through a switch in the differentiation of BMSCs. The bone/fat switch causes bone growth defects and disordered bone metabolism in bone marrow, for which the mechanisms remain unclear, and treatments are lacking. Studies suggest that small non-coding RNAs (microRNAs) could participate in regulating BMSC differentiation by disrupting the post-transcription of target genes, leading to bone/fat formation changes. This review presents an emerging concept of microRNA regulation in the bone/fat formation switch in bone marrow, the evidence for which is assembled mainly from in vivo and in vitro human or animal models. Characterization of changes to microRNAs reveals novel networks that mediate signalling and factors in regulating bone/fat switch and homeostasis. Recent advances in our understanding of microRNAs in their control in BMSC differentiation have provided valuable insights into underlying mechanisms and may have significant potential in development of new therapeutics.

scholarly journals Preclinical Evidence of Nanomedicine Formulation to Target Mycobacterium tuberculosis at Its Bone Marrow Niche

Pathogens ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 372 ◽  
Author(s):  
Jaishree Garhyan ◽  
Surender Mohan ◽  
Vinoth Rajendran ◽  
Rakesh Bhatnagar
Keyword(s):  
Bone Marrow ◽  
Mycobacterium Tuberculosis ◽  
In Vitro Release ◽  
Bone Marrow Niche ◽  
Mice Model ◽  
Latently Infected ◽  
Marrow Mesenchymal Stem Cells

One-third of the world’s population is estimated to be latently infected with Mycobacterium tuberculosis (Mtb). Recently, we found that dormant Mtb hides in bone marrow mesenchymal stem cells (BM-MSCs) post-chemotherapy in mice model and in clinical subjects. It is known that residual Mtb post-chemotherapy may be responsible for increased relapse rates. However, strategies for Mtb clearance post-chemotherapy are lacking. In this study, we engineered and formulated novel bone-homing PEGylated liposome nanoparticles (BTL-NPs) which actively targeted the bone microenvironment leading to Mtb clearance. Targeting of BM-resident Mtb was carried out through bone-homing liposomes tagged with alendronate (Ald). BTL characterization using TEM and DLS showed that the size of bone-homing isoniazid (INH) and rifampicin (RIF) BTLs were 100 ± 16.3 nm and 84 ± 18.4 nm, respectively, with the encapsulation efficiency of 69.5% ± 4.2% and 70.6% ± 4.7%. Further characterization of BTLs, displayed by sustained in vitro release patterns, increased in vivo tissue uptake and enhanced internalization of BTLs in RAW cells and CD271+BM-MSCs. The efficacy of isoniazid (INH)- and rifampicin (RIF)-loaded BTLs were shown using a mice model where the relapse rate of the tuberculosis was decreased significantly in targeted versus non-targeted groups. Our findings suggest that BTLs may play an important role in developing a clinical strategy for the clearance of dormant Mtb post-chemotherapy in BM cells.

Prospective In Vivo Identification of Osteogenic Stem/Progenitor Cells from Bone Marrow-Derived Lin−/Sca-1+/CD45− Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1409-1409
Author(s):  
Zhuo Wang ◽  
Junghun Jung ◽  
Magdalena Kucia ◽  
Junhui Song ◽  
Yusuke Shiozawa ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Bone Formation ◽  
Cultured Cells ◽  
Fluorescent Microscopy ◽  
Micro Ct ◽  
Mineralized Tissue

Abstract We previously developed an in vivo prospective assay for identification of non-cultured cells with MSC potential. Using this assay we identified a population of cells that were slowly cycling and of low density that were capable of multilineage differentiation both in vitro and in vivo (Z. Wang et al, Stem Cells. 2006 24(6):1573). Further characterization of these cells suggested that they resemble a homogenous population of rare Lin−/Sca-1+/CD45− cells that have the morphology and express several markers of undifferentiated embryonic-like stem cells. In vitro the Lin−/Sca-1+/CD45− cells may differentiate into cells from all three germ-layers (M. Kucia et al, Leukemia. 2007 21(2):297). To determine the in vivo fate of this population, we transplanted 500 or 5,000 Lin−/Sca-1+/CD45− cells from a GFP mouse into SCID mice in each group (n=3) immediately after cell sorting to evaluate tissue generation in vivo. At 4 weeks the regenerative potential of these populations was evaluated by micro-CT and histology, and cells were tracked by gross examination of the harvested tissues by fluorescent microscopy. The results showed that a large number of GFP+ cells are located in the implants, indicating that the transplanted cells maintain the ability to contribute to the generation of new tissue. Bone-like tissue was observed in the Lin−/Sca-1+/CD45− group with as low as 500-cells/implant, while 5,000 Lin−/Sca-1+/CD45− cells generated significantly larger mineralized tissue volume, which was confirmed by micro-CT. Lin−/Sca-1+/CD45+ cell only implantation did not form any mineralized tissue, however, while mixed with 2x106 whole bone morrow cells, positive mineralized tissue occurred. Whole bone marrow mixture also improve bone formation in Lin−/Sca-1+/CD45− cell implants compared the actual bone volumes measured by micro-CT. This study demonstrates that non-cultured BM-derived Lin−/Sca-1+/CD45− cells exhibit the capacity to form bone in vivo with as low as 500 cells/implant. Whole bone marrow mixtures can enhance the bone formation, presumably through the interaction of other populations cells. Based on these findings, it is proposed that non-cultured BM-derived Lin−/Sca-1+/CD45− cells are enriched osteogenic cells that can be applied to bone regeneration in vivo.

scholarly journals PRIC295, a Nuclear Receptor Coactivator, Identified from PPAR-Interacting Cofactor Complex

PPAR Research ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-16 ◽  
Author(s):  
Sean R. Pyper ◽  
Navin Viswakarma ◽  
Yuzhi Jia ◽  
Yi-Jun Zhu ◽  
Joseph D. Fondell ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nuclear Receptor Coactivator ◽  
Evolutionarily Conserved

The peroxisome proliferator-activated receptor- (PPAR) plays a key role in lipid metabolism and energy combustion. Chronic activation of PPAR in rodents leads to the development of hepatocellular carcinomas. The ability of PPAR to induce expression of its target genes depends on Mediator, an evolutionarily conserved complex of cofactors and, in particular, the subunit 1 (Med1) of this complex. Here, we report the identification and characterization of PPAR-interacting cofactor (PRIC)-295 (PRIC295), a novel coactivator protein, and show that it interacts with the Med1 and Med24 subunits of the Mediator complex. PRIC295 contains 10 LXXLL signature motifs that facilitate nuclear receptor binding and interacts with PPAR and five other members of the nuclear receptor superfamily in a ligand-dependent manner. PRIC295 enhances the transactivation function of PPAR, PPAR, and ER. These data demonstrate that PRIC295 interacts with nuclear receptors such as PPAR and functions as a transcription coactivator underin vitroconditions and may play an important role in mediating the effectsin vivoas a member of the PRIC complex with Med1 and Med24.

Isolation, Differentiation, and Characterization of Human Bone Marrow Stem Cells In Vitro and In Vivo

2019 ◽  
pp. 53-70 ◽  
Author(s):  
Janos Kanczler ◽  
Rahul S. Tare ◽  
Patrick Stumpf ◽  
Timothy J. Noble ◽  
Cameron Black ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Bone Marrow Stem Cells ◽  
Human Bone ◽  
Human Bone Marrow

scholarly journals CaM kinase II regulates cardiac hemoglobin expression through histone phosphorylation upon sympathetic activation

2019 ◽  
Vol 116 (44) ◽  
pp. 22282-22287
Author(s):  
Ali Reza Saadatmand ◽  
Viviana Sramek ◽  
Silvio Weber ◽  
Daniel Finke ◽  
Matthias Dewenter ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Target Genes ◽  
Ventricular Myocardium ◽  
Cam Kinase Ii ◽  
Sympathetic Activation ◽  
Cam Kinase ◽  
In Vivo Experiments ◽  
Underlying Mechanisms

Sympathetic activation of β-adrenoreceptors (β-AR) represents a hallmark in the development of heart failure (HF). However, little is known about the underlying mechanisms of gene regulation. In human ventricular myocardium from patients with end-stage HF, we found high levels of phosphorylated histone 3 at serine-28 (H3S28p). H3S28p was increased by inhibition of the catecholamine-sensitive protein phosphatase 1 and decreased by β-blocker pretreatment. By a series of in vitro and in vivo experiments, we show that the β-AR downstream protein kinase CaM kinase II (CaMKII) directly binds and phosphorylates H3S28. Whereas, in CaMKII-deficient myocytes, acute catecholaminergic stimulation resulted in some degree of H3S28p, sustained catecholaminergic stimulation almost entirely failed to induce H3S28p. Genome-wide analysis of CaMKII-mediated H3S28p in response to chronic β-AR stress by chromatin immunoprecipitation followed by massive genomic sequencing led to the identification of CaMKII-dependent H3S28p target genes. Forty percent of differentially H3S28p-enriched genomic regions were associated with differential, mostly increased expression of the nearest genes, pointing to CaMKII-dependent H3S28p as an activating histone mark. Remarkably, the adult hemoglobin genes showed an H3S28p enrichment close to their transcriptional start or end sites, which was associated with increased messenger RNA and protein expression. In summary, we demonstrate that chronic β-AR activation leads to CaMKII-mediated H3S28p in cardiomyocytes. Thus, H3S28p-dependent changes may play an unexpected role for cardiac hemoglobin regulation in the context of sympathetic activation. These data also imply that CaMKII may be a yet unrecognized stress-responsive regulator of hematopoesis.

Abstract WMP44: Mir-145 Mediates Bone-marrow-stromal Cell Derived From Type-one Diabetes (t1dm) Rats Induced Neurorestorative Effects in T1dm Rats

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Chengcheng Cui ◽  
Michael Chopp ◽  
Xinchun Ye ◽  
Alex Zacharek ◽  
Ruizhou Ning ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cortical Neurons ◽  
Target Genes ◽  
Capillary Tube ◽  
Border Zone ◽  
Therapeutic Effects ◽  
Ischemic Brain ◽  
Type One Diabetes

Objective: Treatment of stroke with bone-marrow-stromal cells (BMSCs) derived from type-one diabetes (T1DM) rats (DM-BMSCs) improves functional recovery compared to BMSCs derived from normal rats (Nor-BMSCs) and non treatment T1DM rats. In the study, we tested the mechanisms underlying the benefit of the treatment of T1DM stroke with DM-BMSCs. Methods: T1DM rats induced by streptozocin in male Wistar rats were subjected to 2h middle cerebral artery occlusion (MCAo) and were treated at 24h after MCAo via tail vein with: 1) vehicle control; 2) DM-BMSCs; 3) DM-BMSCs with miR-145 overexpression (miR-145+/+DM-BMSCs)(5x10^6) (n=8/group). A battery of functional tests, vascular,white matter (WM) measurements, and cell culture experiments were performed. Results: In vitro, DM-BMSCs exhibited reduced level of miR-145, and increased survival rate compared to Nor-BMSCs. miR-145+/+DM-BMSCs significantly decreased DM-BMSCs survival. DM-BMSCs media increased capillary tube formation and axonal outgrowth in cultured primary cortical neurons (PCNs) compared to Nor-BMSCs media. While miR-145+/+DM-BMSCs exhibited reverse effects compared to DM-BMSCs media. In vivo, DM-BMSCs improved functional outcome, vascular and WM remodeling in the ischemic border zone (IBZ) compared to T1DM-MCAo rats. However, miR-145+/+DM-BMSCs significantly attenuated DM-BMSCs induced beneficial effects. To further test the underlying mechanism of miR-145 mediated DM-BMSCs induced therapeutic effects in T1DM stroke rats, miR-145 target genes adenosine triphosphate-binding cassette transporter 1 (ABCA1) and insulin-like growth factor 1 receptor (IGFR-1) were measured in IBZ. ABCA1 and IGFR1 have neurorestorative effects. Reduction of IGF1 contributes ABCA1 deficiency induced damage in ischemic brain. We found that DM-BMSCs significantly decreased miR-145, increased ABCA1 and IGFR-1 expression in IBZ compared to Nor-BMSCs. While miR-145+/+DM-BMSCs significantly decreased ABCA1 and IGFR-1 expression in IBZ. Conclusion: DM-BMSCs exhibit decreased miR-145 expression and increase miR-145 target gene ABCA1 and IGFR-1 expression in ischemic brain. The miR-145/ABCA1/IGFR-1 pathway may contribute to DM-BMSCs induced neurorestorative effects in T1DM stroke.

scholarly journals Open the LID: LXRα regulates ChREBPα transactivity in a target gene-specific manner through an agonist-modulated LBD-LID interaction

2019 ◽  
Author(s):  
Qiong Fan ◽  
Rikke C. Nørgaard ◽  
Ivar Grytten ◽  
Cecilie M. Ness ◽  
Christin Lucas ◽  
...  
Keyword(s):  
Target Genes ◽  
Glucose Sensing ◽  
Activation Domains ◽  
Specific Target ◽  
Glucose And Lipid Metabolism ◽  
Element Binding Protein ◽  
Underlying Mechanisms ◽  
Responsive Element

ABSTRACTThe cholesterol-sensing nuclear receptor liver X receptor (LXR) and the glucose-sensing transcription factor carbohydrate responsive element-binding protein (ChREBP) are central players in regulating glucose and lipid metabolism in liver. We have previously shown that LXR regulates ChREBP transcription and activity; however, the underlying mechanisms are unclear. In the current study, we demonstrate that LXRα and ChREBPα interact physically, and show a high co-occupancy at regulatory regions in the mouse genome. LXRα co-activates ChREBPα, and regulates ChREBP-specific target genes in vitro and in vivo. This co-activation is dependent on functional recognition elements for ChREBP, but not for LXR, indicating that ChREBPα recruits LXRα to chromatin in trans. The two factors interact via their key activation domains; ChREBPα’s low glucose inhibitory domain (LID) and the ligand-binding domain (LBD) of LXRα. While unliganded LXRα co-activates ChREBPα, ligand-bound LXRα surprisingly represses ChREBPα activity on ChREBP-specific target genes. Mechanistically, this is due to a destabilized LXRα:ChREBPα interaction, leading to reduced ChREBP-binding to chromatin and restricted activation of glycolytic and lipogenic target genes. This ligand-driven molecular switch highlights an unappreciated role of LXRα that was overlooked due to LXR lipogenesis-promoting function.

scholarly journals The Coxiella burnetii QpH1 plasmid is a virulence factor for colonizing bone marrow-derived murine macrophages

2020 ◽  
Author(s):  
Shengdong Luo ◽  
Zhihui Sun ◽  
Huahao Fan ◽  
Shanshan Lu ◽  
Yan Hu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Coxiella Burnetii ◽  
Virulence Factor ◽  
Critical Role ◽  
Murine Macrophages ◽  
Infection Models

AbstractCoxiella burnetii carries a large conserved plasmid or plasmid-like chromosomally integrated sequence of unknown function. Here we report the curing of QpH1 plasmid from C. burnetii Nine Mile phase II, the characterization of QpH1-deficient C. burnetii in in vitro and in vivo infection models, and the characterization of plasmid biology. A shuttle vector pQGK, which is composed of the CBUA0036-0039a region (predicted for QpH1 maintenance), an E. coli plasmid ori, eGFP and kanamycin resistance genes was constructed. The pQGK vector can be stably transformed into Nine Mile II and maintained at a similar low copy like QpH1. Importantly, transformation with pQGK cured the endogenous QpH1 due to plasmid incompatibility. Compared to a Nine Mile II transformant of a RSF1010-based vector, the pQGK transformant shows an identical one-step growth curve in axenic media, a similar growth curve in Buffalo green monkey kidney cells, an evident growth defect in macrophage-like THP-1 cells, and dramatically reduced ability of colonizing bone marrow-derived murine macrophages. In the SCID mouse infection model, the pQGK transformants caused a lesser extent of splenomegaly. Moreover, the plasmid biology was investigated by mutagenesis. We found CBUA0037-0039 are essential for plasmid maintenance, and CBUA0037-0038 account for plasmid compatibility. Taken together, our data suggest that QpH1 encodes factor(s) essential for colonizing murine macrophages, and to a lesser extent for colonizing human macrophages. This study highlights a critical role of QpH1 for C. burnetii persistence in rodents, and expands the toolkit for genetic studies in C. burnetii.Author summaryIt is postulated that C. burnetii recently evolved from an inherited symbiont of ticks by the acquisition of novel virulence factors. All C. burnetii isolates carry a large plasmid or have a chromosomally integrated plasmid-like sequence. The plasmid is a candidate virulence factor that contributes to C. burnetii evolution. Here we describe the construction of novel shuttle vectors that allow to make plasmid-deficient C. burnetii mutants. With this plasmid-curing approach, we characterized the role of the QpH1 plasmid in in vitro and in vivo C. burnetii infection models. We found that the plasmid plays a critical role for C. burnetii growth in macrophages, especially in murine macrophages, but not in axenic media and BGMK cells. Our work highlights an essential role of the plasmid for the acquisition of colonizing capability in rodents by C. burnetii. This study represents a major step toward unravelling the mystery of the C. burnetii cryptic plasmids.

scholarly journals Loss of ERβ expression as a common step in estrogen-dependent tumor progression

2004 ◽  
Vol 11 (3) ◽  
pp. 537-551 ◽  
Author(s):  
A Bardin ◽  
N Boulle ◽  
G Lazennec ◽  
F Vignon ◽  
P Pujol
Keyword(s):  
Tumor Progression ◽  
Target Genes ◽  
Estrogen Receptor Beta ◽  
Estrogen Signaling ◽  
Benign Tumors ◽  
Specific Gene ◽  
Normal Tissues

The characterization of estrogen receptor beta (ERβ) brought new insight into the mechanisms underlying estrogen signaling. Estrogen induction of cell proliferation is a crucial step in carcinogenesis of gynecologic target tissues, and the mitogenic effects of estrogen in these tissues (such as breast, endometrium and ovary) are well documented both in vitro and in vivo. There is also an emerging body of evidence that colon and prostate cancer growth is influenced by estrogens. In all of these tissues, most studies have shown decreased ERβ expression in cancer as compared with benign tumors or normal tissues, whereas ERα expression persists. The loss of ERβ expression in cancer cells could reflect tumor cell dedifferentiation but may also represent a critical stage in estrogen-dependent tumor progression. Modulation of the expression of ERα target genes by ERβ or ERβ-specific gene induction could explain that ERβ has a differential effect on proliferation as compared with ERα. ERβ may exert a protective effect and thus constitute a new target for hormone therapy, such as ligand specific activation. The potential distinct roles of ERα and ERβ expression in carcinogenesis, as suggested by experimental and clinical data, are discussed in this review.

Nonhematopoietic/endothelial SSEA-1+ cells define the most primitive progenitors in the adult murine bone marrow mesenchymal compartment

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 1298-1306 ◽  
Author(s):  
Fernando Anjos-Afonso ◽  
Dominique Bonnet
Keyword(s):  
Bone Marrow ◽  
Mesenchymal Cell ◽  
Cell Types ◽  
Mesenchymal Cells ◽  
Hierarchical Organization ◽  
Mesenchymal Progenitor Cells ◽  
Murine Bone Marrow

Abstract It is believed that a primitive cell type that maintains the mesenchymal compartment exists in the bone marrow. However, this putative mesenchymal stem/progenitor cell is yet to be identified and isolated. We are reporting the identification, isolation, and detailed characterization of the most primitive mesenchymal progenitor cells in the adult murine bone marrow, based on the expression of stage-specific embryonic antigen–1 (SSEA-1). This primitive subset can be identified in mesenchymal cell cultures and also directly in the bone marrow, thus ascertaining for the first time their existence in an adult organism. Characterization of SSEA-1+ mesenchymal cells revealed that upon purification these cells gave rise to SSEA-1− mesenchymal cells, whereas the reverse could not be observed. Also, these SSEA-1+ cells have a much higher capacity to differentiate than their negative counterparts, not only to several mesenchymal cell types but also to unconventional cell types such as astrocyte-, endothelial-, and hepatocyte-like cells in vitro. Most importantly, a single-cell–derived population was capable of differentiating abundantly into different mesenchymal cell types in vivo. Altogether we are proposing a hierarchical organization of the mesenchymal compartment, placing SSEA-1+ cells at the apex of this hierarchy.

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