hAAT-engineered Mesenchymal Stem Cells for the Treatment of Chronic Pain

Ralph H Johnson Va Medical Center, Charleston SC

Investigators

Linked publications & trials

Abstract

One-third of the veterans (~20 million) are suffering from chronic pain. This grant studies chronic pancreatitis (CP)-associated chronic pain in which pain is common and leads to morbidity, poor quality of life, and loss of workdays. Our current VA-funded BLR&D grant is focused on novel stem cell therapy using engineered mesenchymal stem/stromal cells overexpressing human alpha-1 antitrypsin (hAAT-MSCs) in the treatment of chronic pain and pancreas dysfunction in a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced mouse model of CP. To date, we have observed improvement in pain with MSCs which limit the number of mast cells in the pancreatic tissues of mice and downregulate pro-inflammatory pathways in the dorsal root ganglia (DRG) of adjacent neurons. If mast cell-deficient mice are treated with TNBS, then no pain develops and there is less of a high mobility group box 1 (HMGB1) protein response in the DRG that may be responsible for pain sensitization and transition to neuropathic signaling. Therefore, this grant will attempt to integrate inflammatory cell activity in the pancreas with adjacent DRG neuron activation to better understand the metabolic and neuronal signaling that is responsible for chronic pain. Our hope is that the pancreatic inflammation and neuropathic pain mechanisms involved in CP pain are shared with common underlying mechanisms caused by other diseases seen in the VA population. Therefore, CP is a suitable model to study chronic pain, particularly of abdominal origin. Based on current data, the goal for this renewal grant is to further explore the downstream cellular and molecular signaling pathways that mediate the effects of MSC or hAAT-MSCs in reducing chronic pain induced by CP using animal models and cells derived from both mouse and human origins. Discarded painful CP patient- derived pancreatic tissues and patient-specific inducible pluripotent stem cells (iPSC)-derived neuronal organoids will be also used to confirm the finding in mice, and potentially facilitate the translation into humans. Understanding these mechanisms will facilitate the transition of cell therapy to human clinical trials that can target additional Veteran populations suffering from chronic pain. We will test our hypothesis via deciphering the cellular mechanisms of hAAT-MSC protection and activation of mast cells in TNBS-induced CP pain (Aim 1), and by deciphering the role of HMGB1-mediated DRG neuronal activation in the effect of hAAT-MSC in the reduction of pain (Aim 2). These studies will help identify novel mechanisms that contribute to CP pain and understand the mechanistic insights of hAAT-MSCs in modulating pain at both the cellular and the molecular levels.