Overexpression of alpha-1 antitrypsin in mesenchymal stromal cells improves their intrinsic biological properties and therapeutic effects in nonobese diabetic mice.

Abstract

Islet/β cell dysfunction and death caused by autoimmune‐mediated injuries are major features of type 1 diabetes (T1D). Mesenchymal stromal cells (MSCs) have been used for the treatment of T1D in animal models and clinical trials. Based on the anti‐inflammatory effects of alpha‐1 antitrypsin (AAT), we generated human AAT engineered MSCs (hAAT‐MSCs) by infecting human bone marrow‐derived MSCs with the pHAGE CMV‐a1aT‐UBC‐GFP‐W lentiviral vector. We compared the colony forming, differentiation, and migration capacity of empty virus‐treated MSCs (hMSC) and hAAT‐MSCs and tested their protective effects in the prevention of onset of T1D in nonobese diabetic (NOD) mice. hAAT‐MSCs showed increased self‐renewal, better migration and multilineage differentiation abilities compared to hMSCs. In addition, polymerase chain reaction array for 84 MSC‐related genes showed that 23 genes were upregulated, and 3 genes were downregulated in hAAT‐MSCs compared to hMSCs. Upregulated genes include those critical for the stemness (ie, Wnt family member 3A [WNT3A], kinase insert domain receptor [KDR]), migration (intercellular adhesion molecule 1 [ICAM‐1], vascular cell adhesion protein 1 [VICAM‐1], matrix metalloproteinase‐2 [MMP2]), and survival (insulin‐like growth factor 1 [IGF‐1]) of MSCs. Pathway analysis showed that changed genes were related to growth factor activity, positive regulation of cell migration, and positive regulation of transcription. In vivo, a single intravenous infusion of hAAT‐MSCs significantly limited inflammatory infiltration into islets and delayed diabetes onset in the NOD mice compared with those receiving vehicle or hMSCs. Taken together, overexpression of hAAT in MSCs improved intrinsic biological properties of MSCs needed for cellular therapy for the treatment of T1D.