Unravelling mechanisms of stem cell depletion in diabetes
Research type
Research Study
Full title
Unravelling mechanisms of stem cell depletion for preservation of regenerative fitness in patients with diabetes
IRAS ID
126417
Contact name
Paolo Madeddu
Contact email
Sponsor organisation
Research Enterprise Development
Research summary
Research Summary
When a growing fatty plaque or clot blocks the passage of blood in a vessel, the nurtured tissue becomes starved and cells can die. This condition is called ischemia. Medical research is now focusing on stem cells (SC) as a new means to mend the damage caused by ischemia. SC from the bone marrow (BM) are particularly attractive since they participate in processes of vascular repair. In addition, BM SC have been used since long time to treat patients with blood diseases. Recent clinical studies using BM SC in patients with heart attack or limb ischemia show that transplantation of patient's own SC improves the clinical outcome. However, the therapeutic activity of SC might be reduced as a consequence of risk factors. Diabetes mellitus is one major risk factor for ischemic disease. We discovered that SC in BM of diabetic patients are reduced in number and substituted with fat. We also found a reduction of small vessels in BM. Microvascular disease, known as microangiopathy, is responsible for complications of diabetes, such as loss of vision, foot ulcers and renal failure. The goal of the present research is to determine if microangiopathy is the culprit OF SC shortage in the BM of diabetic patients. This could lead to new solutions for preservation of the integrity of BM SC and improvement of current SC-based therapies. To this aim, we will perform a series of laboratory studies on bone surplus from diabetic and non-diabetic patients undergoing orthopaedic surgery at Southmead Hospital (Bristol, UK). These will consist of examining the BM structure by histology and SC and vascular cells in culture. We will also investigate molecular mechanisms that are altered as a consequence of diabetes with the final objective to prevent and reduce the damage induced by high glucose.Summary of Results
Background Cardiac steatosis is an early yet overlooked feature of diabetic cardiomyopathy. There is no available therapy to treat this condition. Tyrosine kinase inhibitors (TKIs) are used as first or second-line therapy in different types of cancer. In cancer patients with diabetes mellitus, TKIs reportedly improved glycemic control, allowing insulin discontinuation. They also reduced liver steatosis in a murine model of non-alcoholic fatty liver disease. The present study aimed to determine the therapeutic effect of the second-generation TKI Dasatinib on lipid accumulation and cardiac function in obese, type 2 diabetic mice. We also assessed if the drug impacts extra-cardiac fat tissue depots.
Methods Two studies on 21-week-old male obese leptin receptor mutant BKS.Cg+Leprdb/+Leprdb/OlaHsd (db/
db) mice compared the effect of Dasatinib (5 mg/kg) and vehicle (10% DMSO + 90% PEG-300) given via gavage once every three days for a week or once every week for four weeks. Functional and volumetric indices were studied using echocardiography. Post-mortem analyses included the assessment of fat deposits and fibrosis using histology, and senescence using immunohistochemistry and flow cytometry. The anti-adipogenic action of Dasatinib was investigated on human bone marrow (BM)-derived mesenchymal stem cells (MSCs). Unpaired parametric or nonparametric tests were used to compare two and multiple groups as appropriate.
Results Dasatinib reduced steatosis and fibrosis in the heart of diabetic mice. The drug also reduced BM adiposity but did not affect other fat depots. These structural changes were associated with improved diastolic indexes, specifically the E/A ratio and non-flow time. Moreover, Dasatinib-treated mice had lower levels of p16 in the heart compared with vehicle-treated controls, suggesting an inhibitory impact of the drug on the senescence signalling pathway. In vitro, Dasatinib inhibited human BM-MSC viability and adipogenesis commitment.
Conclusions Our findings suggest that Dasatinib opposes heart and BM adiposity and cardiac fibrosis. In the heart, this was associated with favourable functional consequences, namely improvement in an index of diastolic function.
Repurposing TKI for cardiac benefit could address the unmet need of diabetic cardiac steatosis.https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fdoi.org%252F10.1186%252Fs12933-023-01955-9%2FNBTI%2F64a7AQ%2FAQ%2F3f455101-113e-47be-9614-010b7890b84e%2F1%2F-eiNHJI504&data=05%7C02%7CWales.REC4%40wales.nhs.uk%7Cdddab9bee39c46ade48308dd556d432d%7Cbb5628b8e3284082a856433c9edc8fae%7C0%7C0%7C638760649979342588%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=29mWGEAzWFd9tcfky9VCoi6XpJTWpraYmv%2FXniI8Aws%3D&reserved=0
REC name
Wales REC 4
REC reference
14/WA/1005
Date of REC Opinion
29 May 2014
REC opinion
Favourable Opinion