Mesenchymal Stem Cells Facilitate Fracture Repair in an Alcohol-Induced Impaired Healing Model

Abstract

Objectives Clinical studies have shown alcohol to be a risk factor for traumatic orthopaedic injuries and for nonunion. Data from animal studies suggest that alcohol exposure inhibits fracture healing. This report presents a novel rodent model of impaired fracture healing caused by repeated alcohol exposure. Using this model, we examined the regenerative effects of an intravenously administered population of isolated and expanded MSCs on fracture healing. Methods Bone marrow-derived MSC were isolated from transgenic Green Fluorescent Protein (GFP) C57BL/6 mice and culture expanded using a lineage depletion protocol. Adult wild-type C57BL/6 mice were subjected to a two-week binge alcohol exposure paradigm, (3 days during which they received daily intraperitoneal injections of a 20% alcohol/saline solution followed by a four-day rest period and another 3 consecutive day binge cycle. At completion of the second binge cycle, mice were subjected to a midshaft tibia fracture while intoxicated. Twenty-four hours following fracture, animals were administered an intravenous (IV) transplant of GFP-labeled MSC. Two weeks following fracture, animals were euthanized and injured tibiae were collected and subjected to biomechanical, histologic, and micro-computed tomography analysis. Results Pre-injury binge alcohol exposure resulted in a significant impairment in biomechanical strength and decrease in callus volume. MSC transplants restored both fracture callus volume (p<0.05) and biomechanical strength (p<0.05) in animals with alcohol-impaired healing. In vivo imaging demonstrated a time-dependent MSC migration to the fracture site. Conclusions These data suggest that a two-week binge alcohol exposure significantly impairs fracture healing in a murine tibia fracture model. IV-administered MSC were capable of specifically homing to the fracture site and of normalizing biomechanical, histologic, and microCT parameters of healing in animals exposed to alcohol. Understanding MSC recruitment patterns and functional contributions to fracture repair may lead to their use in patients with impaired fracture healing and nonunion.

Alcohol Inhibits Osteopontin-dependent Transforming Growth Factor-β1 Expression in Human Mesenchymal Stem Cells

“…Many studies have outlined the ability of MSC to migrate and attach to a fracture environment, thereby contributing to callus formation and healing (30,31). There is much clinical interest in using MSC as an exogenous source to enhance fracture healing, and this has been already shown to partially reverse EtOH-induced deficits in fracture healing in animal models (9). It has been shown that TGF-␤1 contributes to induction of MSC differentiation into several cell lineages (25).…”

“…Differentiation of MSC into osteoblasts and chondrocytes forms the fracture callus, which serves as the scaffolding for bone repair (7,8). Interestingly, exogenous intravenous administration of MSC to alcohol-exposed mice can partly reverse the deficits in fracture healing attributed to alcohol exposure (9). This raises the possibility of MSC use as a treatment modality.…”

Adenovirus-mediated bone morphogenetic protein-2 promotes osteogenic differentiation in human mesenchymal stem cells in vitro

“…Depending on the fracture site, ~5-10% of fractures may result in delayed union or nonunion (2,3). Previously, autogenous bone grafts or free vascularized bone grafts have been widely used for nonunion treatment.…”

Animal models of Alzheimer disease: historical pitfalls and a path forward

“…In addition to the cognitive, sensory, and motor deficits caused by the progression of AD, there are a number of behavioral and psychological symptoms related to dementia. These symptoms include agitation and aggression, wandering, disturbances in the sleep cycle, depression, anxiety, delusions and hallucinations (Ferri et al, 2004;de Vugt et al, 2005;Obermeyer et al, 2012). AD reduces the life expectancy of those affected, with an average survival time after diagnosis of 5-7 years (Fitzpatrick et al, 2005;Ganguli et al, 2005).…”

“…Forgetfulness and difficulties with routine tasks are typically the initial symptoms. As the disease progresses, AD patients develop more severe memory loss, speech impairment, visual and spatial deficits, and loss of coordination and fine motor control (Rossor et al, 1996;Obermeyer et al, 2012;Alzheimer's Disease Internatinal, 2009). In addition to the cognitive, sensory, and motor deficits caused by the progression of AD, there are a number of behavioral and psychological symptoms related to dementia.…”