The International Journal of Biochemistry & Cell Biology 56 (2014) 2–3
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This dedicated issue on Regenerative Medicine: The Challenge of Translation, brings together 16 papers that highlight the breadth of activities in this exciting ﬁeld of tissue regeneration with a strong focus on the realistic capacity for translation to clinical applications. Regenerative medicine is discussed from many perspectives, in a wide range of tissues that include the brain, spinal cord and nerves, eyes, adipose, bone, lungs, skin, heart, skeletal muscles and limbs. The contributions showcase research and other creative activities from around the world and from groups exploring regenerative topics across the vast distance of Australia. Regenerative medicine focuses on the mechanisms whereby adult animals restore form and function to injured tissues and organs after necrosis of post-natal tissues/cells occurs in response to experimental or accidental damage, or disease. The pipeline for regenerative medicine is based upon understanding (1) the molecular control of tissue formation during embryogenesis, postnatal development and ageing, (2) factors involved in regeneration after experimental tissue damage in an evolutionary context, including the use of highly efﬁcient regenerating vertebrate species to analyse mechanisms of repair that often seems remote from a mammalian perspective, and (3) creative application of this biological knowledge, in combination with stem cells, bioengineering and other therapeutic strategies to enhance human tissue regeneration (see Figure 1). Although to date, therapeutically applicable outcomes from this knowledge have been slow to emerge, the reports in this issue illustrate the current interest in the ﬁeld, and its potential for transforming medical practice. Intensive studies of embryogenesis and development in a wide variety of species have provided deep insight into the molecular regulation of speciﬁc tissue formation. It is widely proposed that tissue re-formation during regeneration of post-natal tissues in response to damage recapitulates these molecular events of embryogenesis; however, this is only partially true. While some of the molecular events may be similar, the factors controlling these events may be very different, e.g. inﬂammation plays a vital role during tissue regeneration but is not a feature of tissue embryogenesis/development. The regenerative capacity of young, mature and ageing individuals is inﬂuenced by a host of additional factors that can determine the outcome of tissue repair. The universal aspects of regeneration common to many tissues include (i) events to rapidly limit the extent of initial tissue damage and cell death (e.g. a clot or factors that reduce cell necrosis); (ii) revascularisation to provide oxygen, gas exchange and nutrients; (iii) regulatory networks
http://dx.doi.org/10.1016/j.biocel.2014.10.010 1357-2725/© 2014 Published by Elsevier Ltd.
orchestrated by local immune responses to tissue damage required to remove necrotic cells, help modulate the composition of the extracellular matrix, and facilitate chemotaxis, activation, proliferation and differentiation of the target tissue precursor/stem cells, and ideally to limit ﬁbrosis; (iv) expansion and differentiation of the tissue-speciﬁc precursor/stem cell population regulated by niche signalling molecules; and (v) re-innervation to restore full function. Each of these aspects is differentially affected over time: for example, while many tissue stem cell pools are not depleted with age, the local and humoral factors that control stem cell-mediated repair are often altered in older tissues. The reports in this issue discuss diverse vertebrate animal models that include axolotls, zebraﬁsh, rodents, deer and humans. In mammals, the capacity for regeneration varies markedly between tissues, with some having an excellent capacity (e.g. liver, skin, skeletal muscles) whereas others have little or no ability to replace the critical cells that have died (e.g. cardiomyocytes and many neurons). Where regeneration is unsuccessful, the typical default response in adult mammals is replacement of the specialised tissue-speciﬁc cells by generic ﬁbrous/fatty connective tissue and scar formation. In contrast, other species such as salamanders
Figure 1. Pipeline for Regenerative Medicine: research, mechanisms and clinical translation.
Editorial / The International Journal of Biochemistry & Cell Biology 56 (2014) 2–3
retain a remarkable capacity for regeneration of many tissues including hearts and whole limbs, and adult deer routinely regenerate the bone of antlers: such variability in regenerative strategies may identify new targets for potential therapeutic manipulation in human situations. Much excitement has been generated in the last decade by the regenerative potential of mammalian stem cells, with novel sources including induced pluripotent stem cells and the use of cadavers. The diverse origins of stem cells, their properties, modes of delivery in combination with bioscaffolds, and ability to form speciﬁc adult tissues have dominated many discussions of regeneration. Now attention is shifting to focus on the environment of these stem/precursor cells in vivo in mature and ageing animal tissues. There is a greater emphasis on roles of inﬂammatory/immune cells, the extracellular matrix (also of much interest for bioscaffolds and tissue engineering) and systemic molecules (including hormones and the impact of the microbiome), in controlling the relative success or failure of tissue regeneration in mammals, at different ages and under various conditions of health and disease.
Translation of this knowledge to humans requires deep understanding of all aspects of tissue formation and re-formation in order to develop the best strategies to improve and optimise regeneration of adult and ageing tissues. The challenge is to identify the most critical aspect that needs to be targeted in a given clinical situation. More rigorously deﬁning the successes and problems of clinical translation, will provide a ﬁrm foundation for future applications of dynamic regenerative medicine to human needs. Nadia Rosenthal a,b Australian Regenerative Medicine Institute/EMBL Australia, Monash University, Clayton, VIC 3800, Australia b National Heart and Lung Institute, Imperial College London, W12 0NN, UK a
Miranda D. Grounds c School of Anatomy, Physiology and Human Biology, the University of Western Australia, Perth, WA 6009, Australia
Available online 13 October 2014