ADULT STEM CELL SUPPRESSION DUE TO ALCOHOL INDUCED MICROENVIRONMENT ALTERATIONS

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DESCRIPTION (provided by applicant): Alcoholism and alcohol abuse affect at least 14 million Americans. Chronic alcohol consumption is associated with osteoporosis and an increased rate of lumbar spinal fractures. Posterolateral spinal fusion is the standard treatment for lumbar compression fractures common in ethanol-induced osteoporosis. Chronic alcohol exposure inhibits fracture healing and results in a significantly higher incidence of spinal fusion failures. Costs associated with revision spinal fusion surgery were as high as $72,000 each in 2003. Regenerative medicine is a novel therapeutic modality that employs stem cells to promote tissue healing. Adipose tissue-derived stromal cells (ASCs) promote osteogenesis both in vivo and in vitro. Complex interactions between stem cells and the microenvironment are necessary to enhance osteogenesis, and alterations in either from chronic alcohol exposure can limit their combined efficacy. Based on this knowledge we postulate: (A) That chronic alcohol ingestion reduces the number, rate of expansion, and pleuripotential capacity of ASCs; (B) That chronic alcohol exposure in the recipient inhibits or prevents the acceleration of spinal fusion by application of normal ASCs in a suitable biomaterial carrier; and (C) That ASCs harvested from subjects with chronic alcohol exposure and applied in a suitable biomaterial carrier do not accelerate spinal fusion in normal recipients. These hypotheses will be tested with the following Specific Aims: Aim 1. To determine the effect of chronic alcohol ingestion on ASCs in a rat model. Studies will be performed on cells harvested from normal rats and rats exposed to an established model of chronic alcohol ingestion. The number and behavior of stem cells expanded and passaged in vitro will be quantified with standard procedures. Aim 2. To determine the effect of normal ASCs on spinal fusion in rats with and without chronic alcohol exposure. Studies will be performed with ASCs harvested from subjects with no alcohol exposure implanted into subjects with and without chronic alcohol exposure. Outcome measures of radiographs, micro-CT, RT-PCR, compositional analysis, histology, and immunohistochemistry will provide information surrounding the ability of normal stem cells to induce osteogenesis in normal microenvironments versus microenvironments altered by chronic alcohol exposure. Aim 3. To determine the effect of ASCs harvested from rats with chronic alcohol exposure on spinal fusion in rats with and without chronic alcohol exposure. Studies will be performed with ASCs harvested from subjects with chronic alcohol exposure implanted into subjects with and without chronic alcohol exposure. Outcome measures identical to those of Aim 2 will provide information surrounding the ability of stem cells altered by chronic alcohol exposure to induce osteogenesis in normal versus microenvironments altered by chronic alcohol exposure. Results from this investigation will substantially advance knowledge surrounding alcohol-induced stem cell and matrix alterations that inhibit bone formation. Results from this investigation will contribute substantially to current knowledge surrounding alcohol-induced stem cell and matrix alterations that inhibit bone formation. PUBLIC HEALTH RELEVANCE: Elucidation of the pathophysiology contributing to failure of spinal fusion in the face of chronic alcohol abuse will provide mechanisms to address this important medical problem. Additionally, ASC application is a promising treatment that may accelerate fracture healing in patients with reduced numbers of native osteoblast precursors unrelated to alcohol exposure.