Regenerative Medicine Research最新文献

Stroke, the third leading cause of mortality, is usually associated with severe disabilities, high recurrence rate and other poor outcomes. Currently, there are no long-term effective treatments for stroke. Cell and cytokine therapies have been explored previously. However, the therapeutic outcomes are often limited by poor survival of transplanted cells, uncontrolled cell differentiation, ineffective engraftment with host tissues and non-sustained delivery of growth factors. A tissue-engineering approach provides an alternative for treating ischemic stroke. The key design considerations for the tissue engineering approach include: choice of scaffold materials, choice of cells and cytokines and delivery methods. Here, we review current cell and biomaterial based therapies available for ischemic stroke, with a special focus on tissue-engineering strategies for regeneration of stroke-affected neuronal tissue.

Heart failure (HF) is a serious cardiovascular disease and is characterized by exaggerated sympathetic activity. In this paper, we review these limited studies, with particular emphasis on examining the role of the paraventricular nucleus (PVN) in the neurohumoral excitation in HF. The PVN is an important neuroendocrine and preautonomic output nucleus, and is considered as the important central site for integration of sympathetic nerve activity. Accumulating evidences demonstrate that a number of neurohumoral processes are involved in the pathophysiology of HF, such as renin-angiotensin system (RAS), proinflammatory cytokines (PICs), neurotransmitters, and reactive oxygen species (ROS). Recent studies about neurohumoral regulation indicate that angiotensin II type1 receptor (AT1-R) is the important product mediated by cytoplasmic nuclear factor-kappa B (NF-κB) which is up-regulated along with elevated PICs and angiotensin II (ANG II) in the PVN of HF rats. These findings suggest that the NF-κB mediates the cross-talk between RAS and PICs in the PVN in HF. The further studies indicate that the interaction between AT1-R and NF-κB in the PVN contributes to oxidative stress and sympathoexcitation by modulating neurotransmitters in heart failure, and the superoxide activates NF-κB in the PVN and contributes to neurohumoral excitation. In conclusion, the neurohumoral excitation in HF is based on the interaction of RAS, PICs, ROS, NF-κB and neurotransmitters in the PVN; and the activated NF-κB in the PVN modulates the neurotransmitters and contributes to sympathoexcitation in rats with heart failure.

The prevalence of diabetes continues to increase world-wide and is a leading cause of morbidity, mortality, and rapidly rising health care costs. Although strict glucose control combined with good pharmacological and non-pharmacologic interventions can increase diabetic patient life span, the frequency and mortality of myocardial ischemia and infarction remain drastically increased in diabetic patients. Therefore, more effective therapeutic approaches are urgently needed. Over the past 15 years, cellular repair of the injured adult heart has become the focus of a rapidly expanding broad spectrum of pre-clinical and clinical research. Recent clinical trials have achieved favorable initial endpoints with improvements in cardiac function and clinical symptoms following cellular therapy. Due to the increased risk of cardiac disease, cardiac regeneration may be one strategy to treat patients with diabetic cardiomyopathy and/or myocardial infarction. However, pre-clinical studies suggest that the diabetic myocardium may not be a favorable environment for the transplantation and survival of stem cells due to altered kinetics in cellular homing, survival, and in situ remodeling. Therefore, unique conditions in the diabetic myocardium will require novel solutions in order to increase the efficiency of cellular repair following ischemia and/or infarction. This review briefly summarizes some of the recent advances in cardiac regeneration in non-diabetic conditions and then provides an overview of some of the issues related to diabetes that must be addressed in the coming years.

Regenerative medicine techniques to recover cardiac and vascular function are being increasingly investigated as management strategies for cardiovascular diseases. Circulating endothelial progenitor cells (EPCs) derived from bone marrow are immature cells capable of differentiating into mature endothelial cells and play a role in vascular reparative processes and neoangiogenesis. The potency of EPCs for cardiovascular regeneration has been demonstrated in many preclinical studies and therapeutic utility of EPCs has been evaluated in early-phase clinical trials. However, the regenerative activity and efficiency of the differentiation of EPCs are still limited, and a directed differentiation method for EPCs cells has not been fully demonstrated. In this review, we introduce the role of circulating EPCs as biomarkers of cardiovascular diseases and medical applications of EPCs for cardiovascular regeneration.

The anatomy, function and embryonic development of the heart have been of interest to clinicians and researchers alike for centuries. A beating heart is one of the key criteria in defining life or death in humans. An understanding of the multitude of genetic and functional elements that interplay to form such a complex organ is slowly evolving with new genetic, molecular and experimental techniques. Despite the need for ever more complex molecular techniques some of our biggest leaps in knowledge come from nature itself through observations of mutations that create natural defects in function. Such a natural mutation is found in the Mexican axolotl, Ambystoma mexicanum. It is a facultative neotenous salamander well studied for its ability to regenerate severed limbs and tail. Interestingly it also well suited to studying segmental heart development and differential sarcomere protein expression due to a naturally occurring mendelian recessive mutation in cardiac mutant gene "c". The resultant mutants are identified by their failure to beat and can be studied for extended periods before they finally die due to lack of circulation. Studies have shown a differential expression of tropomyosin between the conus and the ventricle indicating two different cardiac segments. Tropomyosin protein, but not its transcript have been found to be deficient in mutant ventricles and sarcomere formation can be rescued by the addition of TM protein or cDNA. Although once thought to be due to endoderm induction our findings indicate a translational regulatory mechanism that may ultimately control the level of tropomyosin protein in axolotl hearts.

The word "rejuvenate" found in the Merriam-Webster dictionary is (1) to make young or youthful again: give new vigor to, and (2) to restore to an original or new state. Regenerative medicine is the process of creating living, functional tissues to repair or replace tissue or organ function lost due to age, disease, damage, or congenital defects. To accomplish this, approaches including transplantation, tissue engineering, cell therapy, and gene therapy are brought into action. These all use exogenously prepared materials to forcefully mend the failed organ. The adaptation of the materials in the host and their integration into the organ are all uncertain. It is a common sense that tissue injury in the younger is easily repaired and the acute injury is healed better and faster. Why does the elder have a diminished capacity of self-repairing, or why does chronic injury cause the loss of the self-repairing capacity? There must be some critical elements that are involved in the repair process, but are suppressed in the elder or under the chronic injury condition. Rejuvenation of the self-repair mechanism would be an ideal solution for functional recovery of the failed organ. To achieve this, it would involve renewal of the injury signaling, reestablishment of the communication and transportation system, recruitment of the materials for repairing, regeneration of the failed organ, and rehabilitation of the renewed organ. It thus would require a comprehensive understanding of developmental biology and a development of new approaches to activate the critical players to rejuvenate the self-repair mechanism in the elder or under chronic injury condition. Efforts focusing on rejuvenation would expect an alternative, if not a better, accomplishment in the regenerative medicine.

Myocardial infarction (MI) is associated with damage to the myocardium which results in a great loss of functional cardiomyocytes. As one of the most terminally differentiated organs, the endogenous regenerative potentials of adult hearts are extremely limited and insufficient to compensate for the myocardial loss occurring after MI. Consequentially, exogenous regenerative strategies, especially cell replacement therapy, have emerged and attracted increasing more attention in the field of cardiac tissue regeneration. A renewable source of seeding cells is therefore one of the most important subject in the field. Induced pluripotent stem cells (iPSCs), embryonic stem cell (ESC)-like cells that are derived from somatic cells by reprogramming, represent a promising candidate due to their high potentials for self-renewal, proliferation, differentiation and more importantly, they provide an invaluable method of deriving patient-specific pluripotent stem cells. Therefore, iPSC-based cardiac tissue regeneration and engineering has been extensively investigated in recent years. This review will discuss the achievements and current status in this field, including development of iPSC derivation, in vitro strategies for cardiac generation from iPSCs, cardiac application of iPSCs, challenges confronted at present as well as perspective in the future.

Abdominal aortic aneurysm (AAA) is a fatal disease defined as an abdominal aortic diameter of 3.0 cm or more, where the abdominal aorta exceeds the normal diameter by more than 50%. Histopathological changes of AAA mainly include extracellular matrix (ECM) remodeling at the abdominal aorta wall, but there is lack of specific drugs to treat AAA. Recent studies have reported that lysosomal cathepsins could induce vascular remodeling and AAA formation by regulating vascular inflammation, medial smooth muscle cell apoptosis, neovascularization, and protease expression. Thus, cathepsins are expected to become a new therapeutic target for AAA treatment.

Background: Chronic alcohol ingestion may cause severe biochemical and pathophysiological derangements to skeletal muscle. Unfortunately, these alcohol-induced events may also prime skeletal muscle for worsened, delayed, or possibly incomplete repair following acute injury. As alcoholics may be at increased risk for skeletal muscle injury, our goals were to identify the effects of chronic alcohol ingestion on components of skeletal muscle regeneration. To accomplish this, age- and gender-matched C57Bl/6 mice were provided normal drinking water or water that contained 20% alcohol (v/v) for 18-20 wk. Subgroups of mice were injected with a 1.2% barium chloride (BaCl2) solution into the tibialis anterior (TA) muscle to initiate degeneration and regeneration processes. Body weights and voluntary wheel running distances were recorded during the course of recovery. Muscles were harvested at 2, 7 or 14 days post-injection and assessed for markers of inflammation and oxidant stress, fiber cross-sectional areas, levels of growth and fibrotic factors, and fibrosis.

Results: Body weights of injured, alcohol-fed mice were reduced during the first week of recovery. These mice also ran significantly shorter distances over the two weeks following injury compared to uninjured, alcoholics. Injured TA muscles from alcohol-fed mice had increased TNFα and IL6 gene levels compared to controls 2 days after injury. Total protein oxidant stress and alterations to glutathione homeostasis were also evident at 7 and 14 days after injury. Ciliary neurotrophic factor (CNTF) induction was delayed in injured muscles from alcohol-fed mice which may explain, in part, why fiber cross-sectional area failed to normalize 14 days following injury. Gene levels of TGFβ1 were induced early following injury before normalizing in muscle from alcohol-fed mice compared to controls. However, TGFβ1 protein content was consistently elevated in injured muscle regardless of diet. Fibrosis was increased in injured, muscle from alcohol-fed mice at 7 and 14 days of recovery compared to injured controls.

Conclusions: Chronic alcohol ingestion appears to delay the normal regenerative response following significant skeletal muscle injury. This is evidenced by reduced cross-sectional areas of regenerated fibers, increased fibrosis, and altered temporal expression of well-described growth and fibrotic factors.