PMID- 23250986
OWN - NLM
STAT- MEDLINE
DCOM- 20130322
LR  - 20220129
IS  - 1524-4571 (Electronic)
IS  - 0009-7330 (Print)
IS  - 0009-7330 (Linking)
VI  - 112
IP  - 3
DP  - 2013 Feb 1
TI  - Global remodeling of the vascular stem cell niche in bone marrow of diabetic 
      patients: implication of the microRNA-155/FOXO3a signaling pathway.
PG  - 510-22
LID - 10.1161/CIRCRESAHA.112.300598 [doi]
AB  - RATIONALE: The impact of diabetes mellitus on bone marrow (BM) structure is 
      incompletely understood. OBJECTIVE: Investigate the effect of type-2 diabetes 
      mellitus (T2DM) on BM microvascular and hematopoietic cell composition in 
      patients without vascular complications. METHODS AND RESULTS: Bone samples were 
      obtained from T2DM patients and nondiabetic controls (C) during hip replacement 
      surgery and from T2DM patients undergoing amputation for critical limb ischemia. 
      BM composition was assessed by histomorphometry, immunostaining, and flow 
      cytometry. Expressional studies were performed on CD34(pos) immunosorted BM 
      progenitor cells (PCs). Diabetes mellitus causes a reduction of hematopoietic 
      tissue, fat deposition, and microvascular rarefaction, especially when associated 
      with critical limb ischemia. Immunohistochemistry documented increased apoptosis 
      and reduced abundance of CD34(pos)-PCs in diabetic groups. Likewise, flow 
      cytometry showed scarcity of BM PCs in T2DM and T2DM+critical limb ischemia 
      compared with C, but similar levels of mature hematopoietic cells. Activation of 
      apoptosis in CD34(pos)-PCs was associated with upregulation and nuclear 
      localization of the proapoptotic factor FOXO3a and induction of FOXO3a targets, 
      p21 and p27(kip1). Moreover, microRNA-155, which regulates cell survival through 
      inhibition of FOXO3a, was downregulated in diabetic CD34(pos)-PCs and inversely 
      correlated with FOXO3a levels. The effect of diabetes mellitus on anatomic and 
      molecular end points was confirmed when considering background covariates. 
      Furthermore, exposure of healthy CD34(pos)-PCs to high glucose reproduced the 
      transcriptional changes induced by diabetes mellitus, with this effect being 
      reversed by forced expression of microRNA-155. CONCLUSIONS: We provide new 
      anatomic and molecular evidence for the damaging effect of diabetes mellitus on 
      human BM, comprising microvascular rarefaction and shortage of PCs attributable 
      to activation of proapoptotic pathway.
FAU - Spinetti, Gaia
AU  - Spinetti G
AD  - Laboratories of Experimental Cardiovascular Medicine, University of Bristol, 
      Bristol, United Kingdom.
FAU - Cordella, Daniela
AU  - Cordella D
FAU - Fortunato, Orazio
AU  - Fortunato O
FAU - Sangalli, Elena
AU  - Sangalli E
FAU - Losa, Sergio
AU  - Losa S
FAU - Gotti, Ambra
AU  - Gotti A
FAU - Carnelli, Franco
AU  - Carnelli F
FAU - Rosa, Francesco
AU  - Rosa F
FAU - Riboldi, Stefano
AU  - Riboldi S
FAU - Sessa, Fausto
AU  - Sessa F
FAU - Avolio, Elisa
AU  - Avolio E
FAU - Beltrami, Antonio Paolo
AU  - Beltrami AP
FAU - Emanueli, Constanza
AU  - Emanueli C
FAU - Madeddu, Paolo
AU  - Madeddu P
LA  - eng
GR  - PG/09/099/28122/BHF_/British Heart Foundation/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121218
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (Antigens, CD34)
RN  - 0 (Biomarkers)
RN  - 0 (CDKN1A protein, human)
RN  - 0 (CDKN1B protein, human)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p21)
RN  - 0 (FOXO3 protein, human)
RN  - 0 (Forkhead Box Protein O3)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (MIRN155 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27)
SB  - IM
MH  - Adipose Tissue/metabolism/pathology
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antigens, CD34/metabolism
MH  - Apoptosis
MH  - Biomarkers/metabolism
MH  - Bone Marrow Cells/immunology/*metabolism/pathology
MH  - Bone Marrow Examination
MH  - Case-Control Studies
MH  - Cell Lineage
MH  - Cells, Cultured
MH  - Cyclin-Dependent Kinase Inhibitor p21/metabolism
MH  - Cyclin-Dependent Kinase Inhibitor p27/metabolism
MH  - Diabetes Mellitus, Type 2/genetics/*metabolism/pathology
MH  - Diabetic Angiopathies/genetics/*metabolism/pathology
MH  - Endothelial Cells/metabolism/pathology
MH  - Female
MH  - Flow Cytometry
MH  - Forkhead Box Protein O3
MH  - Forkhead Transcription Factors/genetics/*metabolism
MH  - Gene Expression Regulation
MH  - Hematopoietic Stem Cells/immunology/*metabolism/pathology
MH  - Humans
MH  - Immunohistochemistry
MH  - Ischemia/genetics/metabolism/pathology
MH  - Male
MH  - MicroRNAs/genetics/*metabolism
MH  - Microvessels/immunology/*metabolism/pathology
MH  - Middle Aged
MH  - Peripheral Arterial Disease/genetics/metabolism/pathology
MH  - *Signal Transduction
MH  - *Stem Cell Niche
MH  - Transfection
PMC - PMC3616365
MID - EMS52353
OID - NLM: EMS52353
EDAT- 2012/12/20 06:00
MHDA- 2013/03/23 06:00
PMCR- 2013/04/04
CRDT- 2012/12/20 06:00
PHST- 2012/12/20 06:00 [entrez]
PHST- 2012/12/20 06:00 [pubmed]
PHST- 2013/03/23 06:00 [medline]
PHST- 2013/04/04 00:00 [pmc-release]
AID - CIRCRESAHA.112.300598 [pii]
AID - 10.1161/CIRCRESAHA.112.300598 [doi]
PST - ppublish
SO  - Circ Res. 2013 Feb 1;112(3):510-22. doi: 10.1161/CIRCRESAHA.112.300598. Epub 2012 
      Dec 18.