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ABSTRACT Regeneration research is morefocused on translational values. However, lying at its very foundation is anunderstanding of how tissues and organs repair and renew themselves at thecellular level. The past decade has witnessed paradigm changing advances inregenerative biology, many of these stems from novel insights into stemness, pluripotency,cell death and their related intra- and inter-cellular biochemical andmolecular processes. Some of these new insights are highlighted in theparagraphs that follow. We now have a much better understanding of howregeneration occurs in lower organisms. We have also discovered tools and meansof nuclear reprogramming to generate induced pluripotency and changes in cellfate in mammalian models. With further research, there is reasonable hope thatvarious obstacles of regeneration in humans can be better understood andtackled. As regeneration research enters a new era, CellBio welcomes timelyreview articles and original papers on the theme of “The Cell Biology ofRegeneration”. Keywords: Inflammation; Induced Pluripotent Stem (iPS) Cells;Progenitor/Stem Cells; Regeneration; Reprogramming; Wnt 1. Introduction Theability to regenerate injured tissues or organs, as well as rejuvenation of thesenesced or aged, has been an elusive goal of ancient alchemy and modernbiomedicine alike. Biologists have marveled at the ability of plants and loweranimals to regenerate. Planarians and cnidarians could regenerate entireorganism from small body fragments, or even dissociated single cells. However,for more complex animals, this regenerative capacity is apparently attenuated,or completely loss. While organ and limb regeneration are still readilyobserved in fishes, reptiles and amphibians, this almost never occurs to anysignificant extent in mammals. Even at the cellular level, one resigns to thevast amount of data demonstrating that whole tissues aside, most terminallydifferentiated cell types, such as brain neurons and skeletal muscle fibers,simply do not regenerate. While this latter notion remains accurate, the pastfew years have witnessed multiple advances that are paradigm changing in termsof our understanding of regeneration from a cell biological perspective. Thefollowing paragraphs highlight a few aspects of the novel insights associatedwith adult animal regeneration that have become clear after the turn of thecentury. 2. From cNeoblasts to Blastema Stem Cells-Endogenous Pluripotent andMultipotent Stem Cells Enable Regeneration Whether complex tissues could beregenerated appears to depend primarily in the availability of stem cells,their relative lineage differentiation potency, and their state of quiescence(and how this latter state could be changed when the need for regenerationarises). At least in theory, stem/progenitor cells required for regenerationcould exist as an ever present pool, or dedifferentiated from differentiatedcells. To be able to account for their regenerative capacity at the organismallevel, pluripotent, if not totipotent, stem cell types must exist in adultplanarians and cnidarians, and for that matter widely distributed throughoutthe adult organism, Indeed, a population of undifferentiated adult pidingcells, the neoblasts, has been identified to be responsible for planarianregenerative capacity. Using a clonal analysis approach of lethal ionizingradiation followed by single-cell transplan- * A preface to CellBio’s thematicreview series on “The Cell Biology of Regeneration”. Copyright © 2013 SciRes.CellBio 32 B. L. TANG tation in Schmidtea mediterranea, planarian clonogenicneoblasts (cNeoblasts) was shown to be able to differentiated to almost allknown postmitotic cell types throughout the body. Intriguingly, singletransplanted cNeoblasts could restore regeneration in a lethally irradiatedworm [1]. On the other hand, tissue pluripotency in the cnidarian Hydrainvolves three independent cell lineages form the body of the polyp, namelyepithelial stem cells from the ectodermal and endodermal layers respectively,as well as interstitial stem cells [2]. The epithelial stem cells arepluripotent [3] but the interstitial cells at best multipotent. At a level ofmore modest regenerative capacity, reptiles and amphibians are able to generatesevered limbs or other appendages. This is no mean feat as vertebrateappendages are composed of a mixture of tissue types from multiple germ layers.Regeneration in this regard is also dependent on resident stem cells [4]. Theprocess begins with the formation of a blastema at the site if injury oramputation, which is a collection of progenitor cells that appear to be homogenous,but these are at best multipotent, with a good degree of lineage potentialrestriction [5]. The equivalent of a pluripotent planarian eNeoblast is mostlikely either completely absent in adult vertebrate tissues, or is notavailable in any significant numbers that would enable regeneration at a moremassive scale. In mammals, limb regeneration is further reduced to the abilityto regenerate digit tips, and this was recently shown to occur via ectodermaland mesodermal fate-restricted progenitors that regenerate their own lineageswithin the digit tip [6]. It is speculative at the moment as to whyregenerative capacity reduces with complexity, or that a phenotype of havingpluripotent stem cells at stock was selected against in higher vertebrates. Onereason could be the difficulty in the maintenance of a large amount ofpluripotent stem cells quiescent and the increase probability of malignanttransformation. Understanding more about how lower organisms use theirendogenous stem cells to regenerate may provide clues as to how endogenous stemcells in various niches of the adult human could be harness (or activated) toaid regeneration. 3. Rising from the Ashes of the Dead Injury often causesmassive cell death. Attraction of immune cells to the site of injury underliesthe associated inflammatory responses, which together create a nonconducivepost-injury environment that is conventionally viewed to be hostile, impairingthe survival of spared cells as well as anti-proliferative against regeneratingcells. This view may be overtly oversimplified, as recent work suggest thatboth apoptosis (or more accurately, programmed cell death) and inflammationplay important roles in triggering regeneration from cnidarian to vertebrates.Midgastric bisection of Hydra precipitates a rapid wave of apoptosis andtransient release of Wnt3 among interstitial cells at the head regeneratingend, and the latter activates the canonical Wnt/β-catenin pathway inneighbouring cycling cells to enhance cell cycle progression [7]. This sort ofapoptotic cell-induced compensatory cell proliferation has also been documentedin regeneration models of higher organisms, including Drosophila wing discregeneration [8] and tail regeneration in the tadpoles of Xenopus laevis [9].The adult mammalian brain is a well-known organ where regeneration isparticularly restrictive. In fact, it was believed for a long time prior to theidentification and characterization of adult neurogenic regions that adultneurogenesis (i.e. the formation of new neurons from progenitors) [10] does notoccur in the mammalian brain. The much simpler fish brain, on the other hand,could regenerate to a significant degree. Neuroinflammation characterizingcases of acute ischemic or traumatic injuries, as well as more chronicneurodegenerative diseases in human brain pathology, is widely recognized as amajor barrier to regeneration of any kind. Interestingly, recent findingspoints to inflammation as being required and sufficient for enhancing theproliferation of neural progenitors and their subsequent neurogenesis in theadult zebra fish brain [11]. In connection with apoptosisdriven regenerationdiscussed above, Wnt signalling appears to be a key pathway in balancing braindamage and repair. Exogenous Wnt3a injected into mouse striatum was recentlyshown to enhance neurogenesis and significantly functional recovery afterischemic injury [12]. Wnt signalling components are only present in immunecells as well as brain glia cells in adult mammals, and the crosstalk between thesecells in a post-injury inflammatory setting, particularly in influencingneurogenesis [13,14], could be exploited for therapeutic intervention purposes.Regenerative capacities are not only conserved between lower vertebrates andmammals in terms of signalling. It is worth noting that both neurogenic adultneural progenitors in fish and mammals have a similar morphological phenotypeand niche—they all appear to be derived from ventricular radial glia [15,16].4. Starting Over-Nuclear Reprogramming to Pluripotency, Multipotency orAlternative Fates Erasure of epigenetic markings of differentiation and aging,as well as induction of pluripotency, occur naturally during reproduction, beit in the case of a budded Saccharomyces. cerevisiae daughter cell or after thefusion of a spermatozoa and an ovum in humans. The ability of an enucleatedovum to reprogram somatic cell nuclei to a state of pluripotency underlies thepromise of somatic cell nuclear transfer (SCNT) for the generation Copyright ©2013 SciRes. CellBio B. L. TANG 33 of embryonic stem cells, and thus materialsfor autologous transplantation (or for cloning). Just as the community beginsto feel that perhaps efficient SCNT-based reprogramming is for some reasonunachievable for primates and humans, the discovery of induced pluripotency[17] literally changed overnight the way many approach the subject. Thetechnology is based on a deceptively simple concept that nuclear reprogrammingcould be achieved by the introduction and expression of the four Yamanakafactors (Oct3/4, Sox2, Klf4 and c-Myc), or a subset of these in combinationwith others genes/compounds, into easily sampled somatic cells such asfibroblasts or keratinocytes. These genes initiate a cascade of changes ingenetic and epigenetic profiles, converting differentiated somatic cells theseover a period of time into pluripotent stem cells [18]. Work on or related toinduced pluripotent stem (iPS) cells has now amassed more than 4500 PUBMEDentries, and related new findings are being made at an unprecedentedly fastpace. Of particular therapeutic interest is the potential of iPS methods togenerate inpidual-specific autologous cells or tissues that are safe forgrafting. In accordance to the generalized notion that grafting differentiatedcells runs a lower risk of tumorigenesis, researchers quickly develop methodsof direct reprogramming of fibroblast into differentiated cell types of otherlineages, such as neurons [19], cardiomyocytes [20] or endothelial cells [21]without passage through the undifferentiated pluripotent iPS stage.Modifications of factors and culture methods allowed the generation ofmultipotent neural progenitors [22-24] and hematopoietic progenitors [25].Beyond providing therapeutic materials, the seemingly limitless lineageconversion to either fully differentiated cell types or more immediateprogenitors from clinically accessible cells like fibroblasts will also greatlyadvance studies on disease etiology and development. Granted that nuclearreprogramming may be incomplete in the case of iPS cells and residualepigenetic memories of the cell of origin may limit their usefulness, theparadigm shift in terms of research approach using iPS-based methods hasclearly revolutionize regenerative biology. 5. Acknowledgements The author issupported by NUS Graduate School for Integrative Sciences and Engineering(NGS), and declares no conflict of interest.
