Reactive oxygen species adversely impacts bone marrow microenvironment in diabetes

Giuseppe Mangialardi, Gaia Spinetti, Carlotta Reni, Paolo Madeddu, Giuseppe Mangialardi, Gaia Spinetti, Carlotta Reni, Paolo Madeddu

Abstract

Significance: Patients with diabetes mellitus suffer an excess of cardiovascular complications and recover worse from them as compared with their nondiabetic peers. It is well known that microangiopathy is the cause of renal damage, blindness, and heart attacks in patients with diabetes. This review highlights molecular deficits in stem cells and a supporting microenvironment, which can be traced back to oxidative stress and ultimately reduce stem cells therapeutic potential in diabetic patients.

Recent advances: New research has shown that increased oxidative stress contributes to inducing microangiopathy in bone marrow (BM), the tissue contained inside the bones and the main source of stem cells. These precious cells not only replace old blood cells but also exert an important reparative function after acute injuries and heart attacks.

Critical issues: The starvation of BM as a consequence of microangiopathy can lead to a less efficient healing in diabetic patients with ischemic complications. Furthermore, stem cells from a patient's BM are the most used in regenerative medicine trials to mend hearts damaged by heart attacks.

Future directions: A deeper understanding of redox signaling in BM stem cells will lead to new modalities for preserving local and systemic homeostasis and to more effective treatments of diabetic cardiovascular complications.

Figures

FIG. 1.
FIG. 1.
BM microenvironment organization. The BM is spatially organized into different niches. The osteoblastic niche (left) resides in the inner part of BM, lining on the endosteum. It includes the most primitive stem cells and a frame of stromal cells, principally osteoblasts. The vascular niche (right) is constituted by committed progenitor elements that are embedded in a frame of several kinds of stromal cells (ECs, macrophages, perycites, etc.). In both niches, stem and progenitor cells establish cell–cell contacts that are instrumental to reciprocal control of cell function. Ang-1, angiopoietin 1; BM, bone marrow; cKit, stem cell factor receptor; EC, endothelial cell; MMP-9, metalloproteinase 9; N-Cad, N-cadherin; SCF, also known as kit-ligand, stem cell factor; SDF-1, stromal cell-derived factor-1; SDF-1 receptor, CXCR4, C-X-C chemokine receptor type 4; Tie2, angiopoietin receptor 2; VCAM-1, integrin receptor vascular cell adhesion molecule-1; very late antigen-4, Vla-4, integrin alpha4beta1. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
FIG. 2.
FIG. 2.
Oxidative stress network in BM microenvironment. In BM, the sources of ROS are principally represented by the mitochondria and NADPH oxidase catalytic subunit NOX. Superoxide produced is then converted by superoxide dismutase into hydrogen peroxide and scavenged by catalase or glutathione peroxidase. ROS can enhance or decrease stem cell functions by activating or inhibiting different signaling pathways. For example, ROS induce differentiation and migration through the PTEN/PI3K/Akt pathway, sustain quiescence via FOXOs and ATM, and induce senescence through p38 MAPK pathway. ATM, ataxia telangiectasia mutated protein; FOXOs, forkhead box transcription factors; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositide 3-kinase; PTEN, phosphatase and tensin homolog; ROS, reactive oxygen species. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
FIG. 3.
FIG. 3.
Proposed model of microenvironmental alteration in diabetic BM. Representation of endosteal and vascular niches in healthy and diabetic conditions. Different colors identify HSCs (blue), HPCs (green), MSCs (beige), and ECs (brown). Erythrocytes inside the marrow vessels are represented in red. Excessive production of ROS in the marrow microenvironment tends to cause a disruption of stem and progenitor cell homeostasis. The ROS gradient is lost, thus triggering stem cell proliferation and differentiation in areas of the marrow that are devoted to maintaining stem cell quiescence. Furthermore, failure of sinusoidal barrier function causes unselective mobilization, skewed toward inflammatory cells instead of regenerative cells. In addition, microvascular rarefaction causes hypoperfusion and deprives stem cells of necessary trophic inputs, leading to stem cells apoptosis. Altogether, these changes jeopardize the regenerative capacity of BM with consequences for peripheral complications. HPCs, hematopoietic progenitor cells; HSCs, hematopoietic stem cells; MSCs, mesenchymal stem cells. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
FIG. 4.
FIG. 4.
Influence of ROS on microRNA generation. Recent evidence indicates that miRs control several functions of stem cells. ROS can influence the regulation of gene expression through interference of miRs. This influence is exerted at different levels of miR generation and processing. miR, microRNA. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
FIG. 5.
FIG. 5.
Diabetes-induced mobilopathy. Stem and progenitor cell mobilization from BM is a multistep process triggered by a gradient of chemokines generated from ischemic tissues. Chemokines also promote proteolytic activity in the marrow environment, thus favoring stem and progenitor cell relocation from the endosteal niche to the vascular niche and then the passage to the bloodstream. Oxidative stress generated in stem cells by activation of NOX2 acts as a mediator of those chemokines. However, sustained and excessive oxidative stress can lead to eNOS uncoupling, thereby compromising stem cell mobilization. eNOS, endothelial nitric oxide synthase. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

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