Abstract
Ischemia-Reperfusion (IR) injury of limb remains a significant clinical problem causing secondary complications and restricting clinical recovery, despite rapid restoration of blood flow and successful surgery. In an attempt to further improve post ischemic tissue repair, we investigated the effect of a local administration of bone marrow derived stem cells (BMDSCs) in the presence or absence of immune-regulatory enzyme, IDO, in a murine model. A whole limb warm ischemia-reperfusion model was developed using IDO sufficient (WT) and deficient (KO) mice with C57/BL6 background. Twenty-four hours after injury, 5×105 cells (5×105 cells/200 µL of PBS solution) BMDSCs (Sca1 + cells) were injected intramuscularly while the control group received just the vehicle buffer (PBS). Forty-eight to seventy-two hours after limb BMDSC injection, recovery status including the ratio of intrinsic paw function between affected and normal paws, general mobility, and inflammatory responses were measured using video micrometery, flow cytometry, and immunohistochemistry techniques. Additionally, MRI/MRA studies were performed to further study the inflammatory response between groups and to confirm reconstitution of blood flow after ischemia. For the first time, our data, showed that IDO may potentially represent a partial role in triggering the beneficial effects of BMDSCs in faster recovery and protection against structural changes and cellular damage in a hind limb IR injury setting (P = 0.00058).
Highlights
Ischemia-Reperfusion injury is seen in many clinical scenarios from stroke, myocardial infarction, traumatic limb injury, embolic events and organ transplantation
We demonstrated that intramascular injections of bone marrow derived stem cells (BMDSCs) decrease the recovery time after IR injury in hind limb ischemia reperfusion injury
Our results suggest that IDO modulatory feature may play a potential role in beneficial effects of BMDSCs in an ischemia reperfusion setting of hind limb injury, manifested by marked anti-inflammatory effect of these cells and reduction of apoptosis/necrosis inside the tissue microenvironment
Summary
Ischemia-Reperfusion injury is seen in many clinical scenarios from stroke, myocardial infarction, traumatic limb injury, embolic events and organ transplantation. According to statistics from the CDC, nearly 2 million people a year in the US are affected by the above conditions [1]. There is no shortage of opportunity to promote the health and lives of patients under each circumstance by improving our understanding of the mechanisms by which IR injury occurs, so that modulation and attenuation of injury can be achieved for therapeutic purposes. IR injury begins with the initial ischemic event leading to decreased oxygen and nutrient delivery. The resulting metabolic derangements in affected tissues lead to a buildup of acidic metabolites, dysfunction of organelles and build of free radicals, which include reactive oxygen and nitrogen species. Leukocytes become activated releasing cytokines and complement mediators, and inflammatory cascades are activated as a result of cell necrosis
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