Michael Hu

Mechanotransduction and fibrosis

Scarring and tissue fibrosis represent a significant source of morbidity in the United States. Despite considerable research focused on elucidating the mechanisms underlying cutaneous scar formation, effective clinical therapies are still in the early stages of development. A thorough understanding of the various signaling pathways involved is essential to formulate strategies to combat fibrosis and scarring. While initial efforts focused primarily on the biochemical mechanisms involved in scar formation, more recent research has revealed a central role for mechanical forces in modulating these pathways. Mechanotransduction, which refers to the mechanisms by which mechanical forces are converted to biochemical stimuli, has been closely linked to inflammation and fibrosis and is believed to play a critical role in scarring. This review provides an overview of our current understanding of the mechanisms underlying scar formation, with an emphasis on the relationship between mechanotransduction pathways and their therapeutic implications.

Wound healing: an update

Wounds, both chronic and acute, continue to be a tremendous socioeconomic burden. As such, technologies drawn from many disciplines within science and engineering are constantly being incorporated into innovative wound healing therapies. While many of these therapies are experimental, they have resulted in new insights into the pathophysiology of wound healing, and in turn the development of more specialized treatments for both normal and abnormal wound healing states. Herein, we review some of the emerging technologies that are currently being developed to aid and improve wound healing after cutaneous injury.

Biological therapies for the treatment of cutaneous wounds: Phase III and launched therapies

Introduction: Normal wound healing mechanisms can be overwhelmed in the setting of complex acute and chronic tissue injury. Biological therapies are designed to augment and/or restore the bodys natural wound healing abilities. There are a variety of available and emerging technologies utilizing this approach that have demonstrated the ability to augment wound healing. Areas covered: In this review, the clinical data on launched and emerging biological therapies for wound healing applications are summarized. The methodologies discussed include biological skin equivalents, growth factors/small molecules and stem cell-based therapies. Expert opinion: While many products possess convincing clinical data demonstrating their efficacy in comparison to standard treatment options, more robust, controlled studies are needed to determine the relative value among established and emerging biological therapies. Future bioengineering and stem cell-based approaches are of particular interest due to the simultaneous correction of multiple deficiencies present in the nonhealing wound.

The role of stem cells in aesthetic surgery: fact or fiction?

Background: Stem cells are attractive candidates for the development of novel therapies, targeting indications that involve functional restoration of defective tissue. Although most stem cell therapies are new and highly experimental, there are clinics around the world that exploit vulnerable patients with the hope of offering supposed stem cell therapies, many of which operate without credible scientific merit, oversight, or other patient protection. Methods: The authors review the potential and the drawbacks of incorporation of stem cells in cosmetic procedures. A review of U.S. Food and Drug Administration–approved indications and ongoing clinical trials with adipose stem cells is provided. Furthermore, a “snapshot” analysis of Web sites using the search terms “stem cell therapy” or “stem cell treatment” or “stem cell facelift” was performed. Results: Despite the protective net cast by regulatory agencies such as the U.S. Food and Drug Administration and professional societies such as the American Society of Plastic Surgeons, the authors are witnessing worrying advertisements for procedures such as stem cell face lifts, stem cell breast augmentations, and even stem cell vaginal rejuvenation. The marketing and promotion of stem cell procedures in aesthetic surgery is not adequately supported by clinical evidence in the majority of cases. Conclusions: Stem cells offer tremendous potential, but the marketplace is saturated with unsubstantiated and sometimes fraudulent claims that may place patients at risk. With plastic surgeons at the forefront of stem cell–based regenerative medicine, it is critically important that they provide an example of a rigorous approach to research, data collection, and advertising of stem cell therapies.

Abstract 10: Global and Endothelial Cell Specific Deletion of SDF-1 Results in Delayed Wound Healing.

Zeshaan N Maan, MBBS, MS, MRCS1; Natalie Ho, High school1; Robert C Rennert, BA1; Dominik Duscher, MD1; Michael Sorkin, MD1; Melanie Rodrigues, PhD1; Jerry Chen, MD1; Ivan N Vial, MD2; Michael Januszyk, MD1; Michael Findlay, MBBS, PhD1; Michael Hu, MD1; Graham Walmsley, BA1; Michael T Longaker, MD, MBA1; Geoffrey C Gurtner, MD, FACS1 1Stanford University School of Medicine, Stanford, CA, University of Pittsburgh, Pittsburgh, PA

Abstract 135: improved engraftment of autologous skin grafts in diabetic mice with adipose-derived stem cells.

PurPose: Non-healing diabetic wounds are a major health concern in the US, affecting over 1 in 10 diabetic patients. With the increasing prevalence of diabetes, a significant rise in the number of diabetic patients suffering from non-healing wounds is also expected to occur. However, therapies currently available to diabetics are often insufficient to ensure satisfactory wound healing. Thus there is an urgent need for novel therapeutic strategies to address non-healing diabetic wounds. Autologous full thickness skin grafts are one of the most common procedures used for wound closure in both diabetic and nondiabetic patients. However, in diabetic patients skin graft rejection is common because of poor circulation around the graft and surrounding wound areas. One strategy that has been identified as particularly promising has been a cell-based therapeutic approach utilizing adipose-derived stem cells (ASCs). ASCs are an abundant and easily accessible population of adult pluripotent stem cells present in stromal tissue. They can be readily isolated from patients through minimally invasive techniques, potentially allowing for autologous transplantation. ASCs have been shown to promote wound healing in hypoxic environments by releasing various cytokines and growth factors at the wound to promote neovascularization. However, whether ASCs can increase the success of autologous full thickness skin grafts in a diabetic setting remains unclear. In this study we examine the ability of ASCs to mediate acceptance of autologous skin grafts in both wild-type and diabetic mice.

Abstract P44: Improved Wound Healing by Transplantation of Macrophages

PurPose: In obstetrical brachial plexus injuries, the nerves of newborns are stretched and sometimes ruptured. These injuries can be devastating, with more than 25% of infants being left with permanent neurological deficits and potentially chronic pain in the future. Unlike adults, peripheral nerve crush injuries in neonates have demonstrated significant retrograde neuronal death after injury, robbing the nervous system of crucial regenerative components. Loss of viable neurons has been largely overlooked as a cause of morbidity following proximal nerve injuries in newborns. Previous studies have suggested that neonatal susceptibility to motor neuron death after crush injury does not extend past postnatal day 5 (P5) and the time-course of sensory neuron death is poorly understood. We sought to further examine central motor and sensory neuron survival in neonatal crush injuries after P5 and to assess axonal regeneration and functional recovery of behavior and muscle parameters following injury.

Abstract 161: identification of cell-intrinsic mechanisms and differentially regulated genetic pathways responsible for the age-related functional decline in aged skeletal stem cells.

PurPose: Aging is associated with a gradual loss of homeostatic mechanisms that maintain the structure and function of adult tissues. Most adult tissues contain resident stem cells, which proliferate to compensate for tissue loss throughout the life of the organism. It is believed that both chronological aging and replicative aging of adult stem cells negatively affects their functional capacity for tissue regeneration. Natural aging has a profound effect on skeletal healing, evidenced by the reduced healing ability with advancing age, and an increased incidence of osteoporosis. In mice, we have identified a resident stem-cell pool in skeletal tissue. We can successfully isolate a highly-purified population of skeletal stem cells that have the ability of forming bone, cartilage, stroma and a functioning bone marrow cavity at the clonal level. This study examines the cell-intrinsic mechanisms, and the role of the extrinsic stem cell niche on influencing skeletal stem cell aging. The aim of this study is to identify potential pathways that could be manipulated to reverse the effects of skeletal stem cell aging.

Understanding regulatory pathways of neovascularization in diabetes

Diabetes mellitus and its associated comorbidities represent a significant health burden worldwide. Vascular dysfunction is the major contributory factor in the development of these comorbidities, which include impaired wound healing, cardiovascular disease and proliferative diabetic retinopathy. While the etiology of abnormal neovascularization in diabetes is complex and paradoxical, the dysregulation of the varied processes contributing to the vascular response are due in large part to the effects of hyperglycemia. In this review, we explore the mechanisms by which hyperglycemia disrupts chemokine expression and function, including the critical hypoxia inducible factor-1 axis. We place particular emphasis on the therapeutic potential of strategies addressing these pathways; as such targeted approaches may one day help alleviate the healthcare burden of diabetic sequelae.