Global Remodeling of the Vascular Stem Cell Niche in Bone Marrow of Diabetic Patients Implication of the microRNA-155/FOXO3a Signaling Pathway

Gaia Spinetti, Daniela Cordella, Orazio Fortunato, Elena Sangalli, Sergio Losa, Ambra Gotti, Franco Carnelli, Francesco Rosa, Stefano Riboldi, Fausto Sessa, Elisa Avolio, Antonio Paolo Beltrami, Costanza Emanueli, Paolo Madeddu*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

82 Citations (Scopus)

Abstract

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. (Circ Res. 2013;112:510-522.)

Original languageEnglish
Pages (from-to)510-22
Number of pages13
JournalCirculation Research
Volume112
Issue number3
DOIs
Publication statusPublished - 1 Feb 2013

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Keywords

  • Adipose Tissue
  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, CD34
  • Apoptosis
  • Biological Markers
  • Bone Marrow Cells
  • Bone Marrow Examination
  • Case-Control Studies
  • Cell Lineage
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinase Inhibitor p27
  • Diabetes Mellitus, Type 2
  • Diabetic Angiopathies
  • Endothelial Cells
  • Female
  • Flow Cytometry
  • Forkhead Transcription Factors
  • Gene Expression Regulation
  • Hematopoietic Stem Cells
  • Humans
  • Immunohistochemistry
  • Ischemia
  • Male
  • MicroRNAs
  • Microvessels
  • Middle Aged
  • Peripheral Arterial Disease
  • Signal Transduction
  • Stem Cell Niche
  • Transfection

Cite this

Spinetti, G., Cordella, D., Fortunato, O., Sangalli, E., Losa, S., Gotti, A., Carnelli, F., Rosa, F., Riboldi, S., Sessa, F., Avolio, E., Beltrami, A. P., Emanueli, C., & Madeddu, P. (2013). Global Remodeling of the Vascular Stem Cell Niche in Bone Marrow of Diabetic Patients Implication of the microRNA-155/FOXO3a Signaling Pathway. Circulation Research, 112(3), 510-22. https://doi.org/10.1161/CIRCRESAHA.112.300598