Hematopoietic stem cell‑based angiotensin‑(1‑7) delivery to the brain improves functional outcomefollowing cerebral ischemia

Abstract

Angiotensin‑(1‑7) [Ang‑(1‑7)] exerts physiological effects in the brain mediated by its receptor, Mas. Recent studies have successfully demonstrated that Ang‑(1‑7) exerts neuroprotective effects following cerebral ischemia in a rat model. However, prior investigations utilized direct intracerebral cannulation for Ang‑(1‑7) delivery, potentially limiting human application. Hematopoietic stem cells (HSC) have been previously demonstrated to mobilize to the site of cerebral injury in response to stroke. Therefore, we sought to examine the therapeutic potential of HSC transduced via a lentivirus with Ang‑(1‑7) to migrate to the ischemic hemisphere and overexpress Ang‑(1‑7) following stroke. Animals were divided into 3 groups: Stroke + PBS, Stroke + HSC, Stroke + Ang‑(1‑7)‑transduced HSC. Bone marrow from separate animals was harvested and used for injection of the HSC, with or without lentivirus induced Ang‑(1‑7) transduction. A neurological assessment was performed at 72 hours post‑surgery. Ang‑(1‑7) transduced HSC secreted the peptide up to 72 hours post infection, in vitro. Stroked animals injected with the Ang‑(1‑7) infected HSC exhibited reduced behavioral deficits on the Bederson neurological assessment scale. These data suggest that HSC‑mediated delivery of Ang‑(1‑7) to ischemic brain appears to improve post‑stroke outcomes and may offer a novel route of therapeutic agent delivery to the brain.