Lipogems, a new modality of fat tissue handling to enhance tissue repair in chronic hind limb ischemia
Background: Human adipose-derived stem cells (hASCs) may represent an easy-to-harvest tool for cell therapy of peripheral artery disease. In most clinical trials, stem cells undergo prolonged ex vivo expansion, with significant senescence, and decline in multipotency, leading to clinical results below expectations.
Methods: We have developed a non-enzymatic method yielding a microfractured fat tissue (Lipogems), harboring intact stromal-vascular niche and pericyte/mesenchymal stem cells. Human Lipogems, Lipogems-derived hASCs preconditioned with or without a vasculogenic mixture, including hyaluronan, butyric and retinoic acids (H+B+R), were transplanted into the gracilis muscle of 16 rats subjected to chronic hind limb ischemia. After two weeks, tissue rescue was assessed by a perivascular flow probe and immunohistochemistry. Coculture of HUVECs with Lipogems or Lipogems-derived hASCs was performed. Vasculogenic gene transcription and secreted cytokines were assessed.
Results: Xenogeneic transplantation of human Lipogems elicited significantly higher muscle tissue repair and lower inflammatory infiltration than expanded Lipogems-derived hASCs, even preconditioned with H+B+R. Lipogems action involved a significantly higher arteriogenic response than that elicited by untreated or preconditioned hASCs.
Although transplanted Lipogems bordered within the external side of collating primary fibers, it led to remarkably better preservation of muscular fiber size than untreated or preconditioned hASCs. Lipogems-derived hASCs responded to vasculogenic agents with increased VEGF, KDR, and HGF transcription, associated with early and long-lasting secretion of the encoded cytokines. In coculture with HUVECs, Lipogems enhanced endothelial cell proliferation remarkably more than untreated or preconditioned hASCs.
Conclusions: Lipogems emerges as a transplantable immunomodulatory fat tissue product with remarkable arteriogenic and paracrine properties for the rescue of ischemic limb.