THE IMPACT OF DIABETES ON PERIVASCULAR STEM CELL NICHE OF THE BONE MARROW (original) (raw)
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Scientific Reports, 2018
This study was designed to assess whether the protective effects of bone marrow-derived mesenchymal stem cells (MSCs) against diabetes could be enhanced by pioglitazone (PIO), a PPARγ agonist. Combined MSCs and PIO treatments markedly improved fasting blood glucose, body weight, lipid profile levels, insulin level, insulin resistance, β cell function. Those protective effects also attenuated both pancreatic lesions and fibrosis in diabetic rats and decreased the depletion of pancreatic mediators of glycemic and lipid metabolism including peroxisome proliferator-activated receptor alpha (PPARα), PGC-1α, GLP-1 and IRS-2. Cardiac biogenesis of diabetic groups was also improved with MSCs and/or PIO treatments as reflected by the enhanced up-regulation of the expressions of cardiac IRS1, Glucose transporter 4, PGC-1, PPARα and CPT-1 genes and the down-regulated expression of lipogenic gene SREBP. The combination of MSCs and PIO also potentiated the decrease of abnormal myocardial pathological lesions in diabetic rats. Similarly, the inhibitory effects of MSCs on diabetic cardiac fibrosis and on the up regulations of TGF-β, collagen I and III gene expressions were partial but additive when combined with PIO. Therefore, combined therapy with PIO and BMCs transplantation could further potentiate the protective benefit of MSCs against diabetes and cardiac damage compared to MSCs monotherapy. Type 2 diabetes mellitus (T2DM) is the most common form of diabetes representing over 90% of all current diabetic cases. Diabetic cardiomyopathy is a major complication and the main cause of mortality among diabetic patients 1. Patients with T2DM have a significantly higher risk of developing cardiovascular disease namely myocardial infarction, heart failure, and stroke 2. The principle etiologies of T2DM incorporate insulin resistance in target tissues, relatively insufficient secretion of insulin, and subsequent decline of pancreatic β-cell function 3,4. Multiple factors contribute to the development of cardiac dysfunction in diabetes including: alteration in lipid and glucose metabolism inside cardiomyocytes, induced oxidative stress, chronic inflammation, collagen deposition and apoptosis 5-7. Insulin resistance in myocardium contributes to the adverse left ventricular remodeling and mitochondrial dysfunction leading to repression of insulin signaling pathways or glucose transporters (GLUTs; such as GLUT1 and GLUT4) in myocardium-mediated glucose transport 8. Metabolic dysregulation occurring in the heart of diabetic patients involves derangements in the activity of peroxisome proliferator-activated receptors (PPARs), PPAR gamma coactivator 1-alpha (PGC-1α), AMP-activated protein kinase (AMPK) and nuclear factor-kB (NF-κB). Consequently, oxidative stress, chronic inflammation, fibrosis, and cell death can be induced and eventually contribute to and exacerbate diabetic
This experiment investigated the impact of serum from patients with type 2 diabetes mellitus on the angiogenic behavior of human mesenchymal stem cells in vitro. Changes in the level of Ang-1, Ang-2, cell migration, and trans-differentiation into pericytes and endothelial lineage were monitored after 7 days. The interaction of mesenchymal stem cells with endothelial cells were evaluated using surface plasmon resonance technique. Paracrine restorative effect of diabetic stem cells was tested on pancreatic b cells. Compared to data from FBS and normal serum, diabetic serum reduced the stem cell survival and chemotaxis toward VEGF and SDF-1a (P < 0.05). Diabetic condition were found to decline cell migration rate and the activity of MMP-2 and-9 (P < 0.05). The down-regulation of VEGFR-2 and CXCR-4 was observed with an increase in the level of miR-1-3p and miR-15b-5p at the same time. The paracrine angiogenic potential of diabetic stem cells was disturbed via the changes in the dynamic of Ang-1, Ang-2, and VEGF. Surface plasmon resonance analysis showed that diabetes could induce an aberrant increase in the interaction of stem cells with endothelial cells. After treatment with diabetic serum, the expression of VE-cadherin and NG2 and ability for uptake of Dil-Ac-LDL were reduced (P < 0.01). Conditioned media prepared from diabetic stem cells were unable to decrease fatty acid accumulation in b-cells (P < 0.05). The level of insulin secreted by b-cells was not affected after exposure to supernatant from diabetic or non-diabetic mesenchymal stem cells. Data suggest diabetes could decrease angiogenic and restorative effect of stem cells in vitro.
The review of diabetic studies, 2009
Cellular microenvironment is known to play a critical role in the maintenance of human bone marrow-derived mesenchymal stem cells (BM-MSCs). It was uncertain whether BM-MSCs obtained from a 'diabetic milieu' (dBM-MSCs) offer the same regenerative potential as those obtained from healthy (non-diabetic) individuals (hBM-MSCs). To investigate the effect of diabetic microenvironment on human BM-MSCs, we isolated and characterized these cells from diabetic patients (dBM-MSCs). We found that dBM-MSCs expressed mesenchymal markers such as vimentin, smooth muscle actin, nestin, fibronectin, CD29, CD44, CD73, CD90, and CD105. These cells also exhibited multilineage differentiation potential, as evident from the generation of adipocytes, osteocytes, and chondrocytes when exposed to line-age specific differentiation media. Although the cells were similar to hBM-MSCs, 6% (3/54) of dBM-MSCs expressed proinsulin/C-peptide. Emanating from the diabetic microenvironmental milieu, we analyzed whether in vitro reprogramming could afford the maturation of the islet-like clusters (ICAs) derived from dBM-MSCs. Upon mimicking the diabetic hyperglycemic niche and the supplementation of fetal pancreatic extract, to differentiate dBM-MSCs into pancreatic lineage in vitro, we observed rapid differentiation and maturation of dBM-MSCs into islet-like cell aggregates. Thus, our study demonstrated that diabetic hyperglycemic microenvironmental milieu plays a major role in inducing the differentiation of human BM-MSCs in vivo and in vitro.
4- Therapeutic Effects of Bone Marrow Stem Cells in Diabetic Rats.pdf
Background: Currently, diabetes mellitus, specifically, Type 2 diabetes is a multifactorial metabolic disorder that affects more than 348 million people worldwide. It is considered to be one of the main causes of mortality. The pathway of type 2 diabetes is characterized both by insulin resistance in muscle, fat, and liver and a relative failure of the pancreatic β cell. Despite extensive study, yet no unifying hypothesis exists to explain these defects and the proper treatment. The key goal of diabetes treatment is to prevent complications because over time, diabetes can damage the heart, blood vessels, eyes, kidneys, and nerves. Therefore there is a great need to develop new and effective therapies for treating diabetic complications early before it cause irreparable tissue damage. Recently, advances experimental evidence empowers the idea that diabetic patients may greatly benefit from cell-based therapies, which include the use of adult stem and/or progenitor cells in disease therapy. In particular, therapeutic effect of bone marrow stem cell in treating the type 2 diabetic patients.
Bone marrow pericyte dysfunction in individuals with type 2 diabetes
Diabetologia
Aims/hypothesis Previous studies have shown that diabetes mellitus destabilises the integrity of the microvasculature in different organs by damaging the interaction between pericytes and endothelial cells. In bone marrow, pericytes exert trophic functions on endothelial cells and haematopoietic cells through paracrine mechanisms. However, whether bone marrow pericytes are a target of diabetes-induced damage remains unknown. Here, we investigated whether type 2 diabetes can affect the abundance and function of bone marrow pericytes. Methods We conducted an observational clinical study comparing the abundance and molecular/functional characteristics of CD146 + pericytes isolated from the bone marrow of 25 individuals without diabetes and 14 individuals with uncomplicated type 2 diabetes, referring to our Musculoskeletal Research Unit for hip reconstructive surgery. Results Immunohistochemistry revealed that diabetes causes capillary rarefaction and compression of arteriole size in bone marrow, without changing CD146 + pericyte counts. These data were confirmed by flow cytometry on freshly isolated bone marrow cells. We then performed an extensive functional and molecular characterisation of immunosorted CD146 + pericytes. Type 2 diabetes caused a reduction in pericyte proliferation, viability, migration and capacity to support in vitro angiogenesis, while inducing apoptosis. AKT is a key regulator of the above functions and its phosphorylation state is reportedly reduced in the bone marrow endothelium of individuals with diabetes. Surprisingly, we could not find a difference in AKT phosphorylation (at either Ser473 or Thr308) in bone marrow pericytes from individuals with and without diabetes. Nonetheless, the angiocrine signalling reportedly associated with AKT was found to be significantly downregulated, with lower levels of fibroblast growth factor-2 (FGF2) and C-X-C motif chemokine ligand 12 (CXCL12), and activation of the angiogenesis inhibitor angiopoietin 2 (ANGPT2). Transfection with the adenoviral vector carrying the coding sequence for constitutively active myristoylated AKT rescued functional defects and angiocrine signalling in bone marrow pericytes from diabetic individuals. Furthermore, an ANGPT2 blocking antibody restored the capacity of pericytes to promote endothelial networking. Conclusions/interpretation This is the first demonstration of pericyte dysfunction in bone marrow of people with type 2 diabetes. An altered angiocrine signalling from pericytes may participate in bone marrow microvascular remodelling in individuals with diabetes.
International Journal of Molecular Sciences
Diabetes strongly contributes to the development of cardiovascular disease, the leading cause of mortality and morbidity in these patients. It is widely accepted that hyperglycemia impairs hematopoietic stem/progenitor cell (HSPC) mobilization from the bone marrow (BM) by inducing stem cell niche dysfunction. Moreover, a recent study demonstrated that type 2 diabetic patients are characterized by significant depletion of circulating provascular progenitor cells and increased frequency of inflammatory cells. This unbalance, potentially responsible for the reduction of intrinsic vascular homeostatic capacity and for the establishment of a low-grade inflammatory status, suggests that bone BM-derived HSPCs are not only victims but also active perpetrators in diabetic complications. In this review, we will discuss the most recent literature on the molecular mechanisms underpinning hyperglycemia-mediated BM dysfunction and differentiation abnormality of HSPCs. Moreover, a section will be ...
PLoS ONE, 2012
Diabetes leads to complications in selected organ systems, and vascular endothelial cell (EC) dysfunction and loss is the key initiating and perpetuating step in the development of these complications. Experimental and clinical studies have shown that hyperglycemia leads to EC dysfunction in diabetes. Vascular stem cells that give rise to endothelial progenitor cells (EPCs) and mesenchymal progenitor cells (MPCs) represent an attractive target for cell therapy for diabetic patients. Whether these vascular stem/progenitor cells succumb to the adverse effects of high glucose remains unknown. We sought to determine whether adult vascular stem/progenitor cells display cellular activation and dysfunction upon exposure to high levels of glucose as seen in diabetic complications. Mononuclear cell fraction was prepared from adult blood and bone marrow. EPCs and MPCs were derived, characterized, and exposed to either normal glucose (5 mmol/L) or high glucose levels (25 mmol/L). We then assayed for cell activity and molecular changes following both acute and chronic exposure to high glucose. Our results show that high levels of glucose do not alter the derivation of either EPCs or MPCs. The adult blood-derived EPCs were also resistant to the effects of glucose in terms of growth. Acute exposure to high glucose levels increased caspase-3 activity in EPCs (1.4x increase) and mature ECs (2.3x increase). Interestingly, MPCs showed a transient reduction in growth upon glucose challenge. Our results also show that glucose skews the differentiation of MPCs towards the adipocyte lineage while suppressing other mesenchymal lineages. In summary, our studies show that EPCs are resistant to the effects of high levels of glucose, even following chronic exposure. The findings further show that hyperglycemia may have detrimental effects on the MPCs, causing reduced growth and altering the differentiation potential.