Regenerative biology and medicine

The replacement of damaged tissues and organs with tissue and organ transplants or bionic implants has serious drawbacks. There is now emerging a new approach to tissue and organ replacement, regenerative biology and medicine. Regenerative biology seeks to understand the cellular and molecular differences between regenerating and non-regenerating tissues. Regenerative medicine seeks to apply this understanding to restore tissue structure and function in damaged, non-regenerating tissues. Regeneration is accomplished by three mechanisms, each of which uses or produces a different kind of regeneration-competent cell. Compensatory hyperplasia is regeneration by the proliferation of cells which maintain all or most of their differentiated functions (e.g., liver). The urodele amphibians regenerate a variety of tissues by the dedifferentiation of mature cells to produce progenitor cells capable of division. Many tissues contain reserve stem or progenitor cells that are activated by injury to restore the tissue while simultaneously renewing themselves. All regeneration-competent cells have two features in common. First, they are not terminally differentiated and can re-enter the cell cycle in response to signals in the injury environment. Second, their activation is invariably accompanied by the dissolution of the extracellular matrix (ECM) surrounding the cells, suggesting that the ECM is an important regulator of their state of differentiation. Regenerative medicine uses three approaches. First is the transplantation of cells into the damaged area. Second is the construction of bioartificial tissues by seeding cells into a biodegradable scaffold where they produce a normal matrix. Third is the use of a biomaterial scaffold or drug delivery system to stimulate regeneration in vivo from regeneration-competent cells. There is substantial evidence that non-regenerating mammalian tissues harbor regeneration-competent cells that are forced into a pathway of scar tissue formation. Regeneration can be induced if the factors leading to scar formation are inhibited and the appropriate signaling environment is supplied. An overview of regenerative mechanisms, approaches of regenerative medicine, research directions, and research issues will be given.     

Extracellular vesicles: Regenerative medicine prospect in hematological malignancies

Extracellular vesicles (EVs) either as endocytic or plasma membrane-emerged vesicles play pivotal role in cell-to-cell communication. Due to the bioactive molecules transformation, lymphoma cell-derived vesicles can alter a recipient cell's function and contribute to signal transduction and drug resistance. These vesicles by acting not only in tumor cells but also in tumor-associated cells have important roles in tumor growth and invasion. On the other hand, the total protein level of circulating exosomes reveals the disease stage, tumor burden, response to therapy, and survival. In residual disease, leukemic blasts are undetectable in the bone marrow by conventional methods but exosomal proteins are elevated significantly. In this manner, new methods for measuring exosomes and exosomal components are required. In this review, we try to reveal the concealed role of EVs in hematological malignancies besides therapeutic potentials.     

Regenerative medicine in the treatment of peripheral arterial disease

The last decade has witnessed a dramatic increase in the mechanistic understanding of angiogenesis and arteriogenesis, the two processes by which the body responds to obstruction of large conduit arteries. This knowledge has been translated into novel therapeutic approaches to the treatment of peripheral arterial disease, a condition characterized by progressive narrowing of lower extremity arteries and heretofore solely amenable to surgical revascularization. Clinical trials of molecular, genetic, and cell‐based treatments for peripheral artery obstruction have generally provided encouraging results. J. Cell. Biochem. 108: 753–761, 2009. © 2009 Wiley‐Liss, Inc.     

Regenerative medicine in China: new advances and hopes

正Tissue and organ repair as well as regeneration are globalfrontiers in the field of stem cell research and regenerativemedicine. Regenerative medicine is closely associated withtreatments of almost all human diseases, injuries, and ag-ing-related problems. The rapid advancements in stem celltechnology, tissue engineering, and physical as well aschemical interventions have resulted in significant progressin tissue and organ repair as well as regeneration. Currently,a single tissue type can be repaired and regenerated throughcell transplantation, trophic factors, biodegradable scaffolds,     

Regenerative medicine based applications to combat stress urinary incontinence

Stress urinary incontinence (SUI), as an isolated symptom, is not a life threatening condition. However, the fear of unexpected urine leakage contributes to a significant decline in quality of life parameters for afflicted patients. Compared to other forms of incontinence, SUI cannot be easily treated with pharmacotherapy since it is inherently an anatomic problem. Treatment options include the use of bio-injectable materials to enhance closing pressures, and the placement of slings to bolster fascial support to the urethra. However, histologic findings of degeneration in the incontinent urethral sphincter invite the use of tissues engineering strategies to regenerate structures that aid in promoting continence. In this review, we will assess the role of stem cells in restoring multiple anatomic and physiological aspects of the sphincter. In particular, mesenchymal stem cells and CD34⁺ cells have shown great promise to differentiate into muscular and vascular components, respectively. Evidence supporting the use of cytokines and growth factors such as hypoxia-inducible factor 1-alpha, vascular endothelial growth factor, basic fibroblast growth factor, hepatocyte growth factor and insulin-like growth factor further enhance the viability and direction of differentiation. Bridging the benefits of stem cells and growth factors involves the use of synthetic scaffolds like poly (1,8-octanediol-co-citrate) (POC) thin films. POC scaffolds are synthetic, elastomeric polymers that serve as substrates for cell growth, and upon degradation, release growth factors to the microenvironment in a controlled, predictable fashion. The combination of cellular, cytokine and scaffold elements aims to address the pathologic deficits to urinary incontinence, with a goal to improve patient symptoms and overall quality of life.     

Regenerative medicine research in China: from basic research to clinical practice

<正>I am very happy to write editorial for this Special Issue of Stem Cells and Regenerative Medicine in China in Science China Life Sciences.As we all know,stem cells and regenerative medicine research is the frontiers not only in China,but also in the world.In recent decades,rapid research progressing,strong governmental support and recruitment of highly trained scientists from abroad together with domestic outstanding researchers and clinicians have made it possible     

Regenerative medicine bioprocessing: Concentration and behavior of adherent cell suspensions and pastes

Regenerative medicines based on human cells demand their harvesting, culture, and processing. Manufacturing processes are likely to include cell concentration and subsequent controlled dosing of concentrates, for example, to the patient or tissue construct. The integrity and functionality of the cells must be maintained during these processing stages. In this study the performance of two different cell concentration protocols (involving centrifugation and resuspension) are compared and consideration given to possible causes of cell loss. Further studies examine cell size and rheological behavior of anchorage‐dependent mammalian cell suspensions, and the effect of capillary flow stress (0.5–15 Pa, laminar flow regime) on cell number and membrane integrity as quantified by flow cytometry. The cell concentration protocols achieved maximum cell volume fraction of around 0.3 and the improved protocol exhibited intact cell yield of 80 ± 13%, demonstrating proof‐of principle for achieving tissue‐like cell concentrations by a process of centrifugation and orbital shaking. Volume mean cell diameter (cell diameter at the mean cell volume) for the rat aortic smooth muscle cells (CRL‐1444) used in this study was 22.4 µm. Concentrated cell suspension rheology approximated to power law behavior and exhibited similar trends to reports for plant and yeast cells. Capillary transfer at 2–15 Pa (wall shear stress) did not significantly affect cell number or membrane integrity while losses observed at low shear (0.5, 1.0 Pa) were probably due to surface attachment of cells in the apparatus. Biotechnol. Bioeng. 2009;103: 1236–1247. © 2009 Wiley Periodicals, Inc.     

Regenerative medicine in multiple sclerosis: identifying pharmacological targets of adult neural stem cell differentiation

Progressive axonal loss from chronic demyelination in multiple sclerosis (MS) is the key contributor to clinical decline. Failure to regenerate myelin by adult oligodendrocyte precursor cells (OPCs), a widely distributed neural stem cell population in the adult brain, is one of the major causes of axonal degeneration. In order to develop successful therapies to protect the integrity of axons in MS, it is important to identify and understand the key molecular pathways involved in myelin regeneration (remyelination) by adult OPCs. This review highlights recent findings on the critical signaling pathways associated with OPC differentiation following CNS demyelination. We discuss the role of LINGO-1, Notch, Wnt, and retinoid X receptor (RXR) signaling, and how they might be useful pharmacological targets to overcoming remyelination failure in MS.     

Regenerative medicine: Evidence for remarkable healing power of adult (somatic) stem cells

There is a little doubt that regenerative medicine primarily based on stem cell-derived therapies would revolutionize health care and prevent thousands, perhaps, millions of human deaths. However, human society is sharply fragmented by the real and imaginary boundaries of social, ethical, political and religious views on how to reach the promise lend of future benefits of regenerative medicine. This sharp division to a large degree is arising from the concept that desired therapeutic gains would not be possible to achieve without exploiting unique healing potentials of embryonic stem cells. The paper published in this issue of Cell Cycle reports experimental findings which seem to challenge this broadly held view¹. Robert Hoffman and colleagues describe the proof of principle experiments in mice demonstrating a remarkable healing power of a cell line which was derived from pluripotent adult (somatic) stem cells and maintained in culture for the extended period of time. The paper represents a logical continuation of the multi-year effort of this team and would be recognized as a breakthrough if these unique and truly fascinating findings will be independently replicated and their relevance will be validated for human conditions. I would like to express one general note of caution that should be exercised when considerations are given for therapeutic applications of stem cells. Growing body of evidence supports the concept that stem cells are the seeds of the most clinically deadly form of therapy-resistant human cancers arising in different organs and rapidly spreading across the human body^2-5. Therefore, potential therapeutic benefits of stem cells should be carefully measured and weighted against the possible side effects for every patient and each disease indication. Our decision making process in disease management should continue to be firmly adhered to the conservative principles of the evidence-based medicine. However, there are circumstances, one example of which is illustrated by this paper¹, when medical and humanitarian necessities would override these concerns. Even the prospect of developing deadly cancer in the future should not stop us from helping human beings who are deprived of the ability to walk, move, or speak.

References

Amoh Y, Li L, Katsuoka K, Hoffman RM. Multipotent hair follicle stem cells promote repair of spinal cord injury and recovery of walking function. Cell Cycle 2008: 7: In this issue.Glinsky GV. Death-from-cancer signatures and stem cell contribution to metastatic cancer. Cell Cycle 2005; 4: 1171-5.Glinsky GV, Glinskii AB, Berezovskaya O. Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. J Clin Invest 2005; 115:1503-21.Glinsky GV. Stem cell origin of death-from-cancer phenotypes of human prostate and breast cancers. Stem Cells Reviews 2007; 3:79-93.Glinsky, GV. “Stemness” genomics law governs clinical behavior of human cancer: Implications for decision making in disease management. J Clin Oncol 2008; In press.