Low Intensity Ultrasound Prolongs Lifetimes of Mesenchymal Stem Cell Transplants Through Interferon-γ and Hypoxia Inducible Factor 1-α Signaling

Authors

• SR Burks
• RM Lorsung
• JA Frank

Abstract

Mesenchymal stem cells (MSC) are currently the most clinically applicable stem cell for transplantation. While MSCs are considered immune privileged and can evade immune surveillance, they do not engraft into host tissue and die within 3-10 days post-transplantation. We found that unfocused therapeutic ultrasound (TUS) exposures to skelatal muscle containing human MSC xenografts prolonged MSC lifetimes over 6 days. We evaluated the proteomic and physiological responses to TUS in skeletal muscle and identified hypoxia inducible factor-1 (HIF1) as a primary driver of increased longevity. Xenotransplantations permits distinguishing molecular changes in MSC grafts versus host muscle tissue. We found that TUS to MSC-containing hamstrings caused hypoxia which upregulated HIF1 in both skeletal muscle cells and transplanted MSC. Using HIF1-KO MSC or digoxin to inhibit HIF1 expression in host tissue, we observed that HIF1 expression was critical in both graft and host. It drove growth factor production by muscle which increased AKT phosphorlyation in MSC. MSC-expressed HIF1 increased MSC Bcl-2 expression to inhibit apoptosis. Lastly, TUS also increased interferon- (IFN) in skeletal muscle. This led to increased programmed-death-receptor ligand-1 (PD-L1) and indoleamine 1, 2 dioxygenase (IDO) in transplanted MSC. In the inflammed parenchyma of mdx mice (a genetic model of muscular dystrophy), TUS upregulated PD-L1 and IDO, which in turn, reduced cytoxic T-cell effects in the muscle. This had the dual effect of prolong MSC lifetimes (as they are succeptible to death by cytotoxic T-cells), but also essentially potentiating therapeutic MSC effects as they are used primarily for anti-inflammatory purposes.

Scientific Focus Area: Biomedical Engineering and Biophysics

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