Adipose Mesenchymal Stromal Cells Isolated From Type 2 Diabetic Patients Display Reduced Fibrinolytic Activity

Stem cells have been successfully used for the treatment of critical limb ischemia (CLI). We conducted a clinical trial to determine the feasibility of using autologous adipose-derived mesenchymal stromal cells (AdMSCs) for the treatment of CLI. Unexpectedly, two diabetic patients developed peripheral microthrombosis. This adverse effect, which contrasts with the reported antithrombotic properties of MSCs, may stem from the diabetic environment that alters the fibrinolytic activity of AdMSCs, thereby increasing the probability of developing thrombosis. Here, we confirm this premise by demonstrating that diabetic AdMSCs cultured in the presence of blood sera expressed and released higher levels of plasminogen activator inhibitor type 1, reduced levels of tissue plasminogen activator, and lower d-dimer formation compared with nondiabetic AdMSCs. Thus, to establish an appropriate cell therapy for diabetic patients, we recommend including new preclinical safety tests, such as the d-dimer and/or the tissue plasminogen activator-to-plasminogen activator inhibitor type 1 ratio tests, to assess fibrinolytic activity of cells before implantation.We evaluated the safety and feasibility of using autologous adipose-derived mesenchymal stromal cells (AdMSCs) for diabetic patients (ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT01257776","term_id":"NCT01257776"}}NCT01257776). Two diabetic patients developed distal microthrombosis (DMT) that was controlled with aggressive antithrombotic therapy. DMT was not detected when autologous AdMSCs isolated from nondiabetic patients were used (ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT01745744","term_id":"NCT01745744"}}NCT01745744) under identical conditions, as reported in ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00872326","term_id":"NCT00872326"}}NCT00872326) (1). Development of AdMSCs-associated DMT has not been previously reported and is in sharp contrast to the described fibrinolytic and antithrombogenic properties of MSCs (2–4). This novel clinical observation raises the possibility that the diabetic milieu of patients may alter the functional properties of AdMSCs, thereby impairing secretion of factors involved in fibrinolysis. To validate this premise, we evaluated whether AdMSCs isolated from diabetic and nondiabetic patients and cultured in the presence of healthy, diabetic, or nondiabetic blood sera displayed differential expression levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI-1), which may result in impaired fibrinolytic activity of AdMSCs derived from diabetic patients.

TABLE 1

Clinical parameters and inclusion and exclusion criteria of diabetic and nondiabetic patients with CLIOpen in a separate window