Regeneration across Metazoan Phylogeny
REVIEW Regeneration across Metazoan Phylogeny: Lessons from Model Organisms
Authors: Qiao Li, Hao Yang, Tao P. Zhong
Affiliations:
a State Key Laboratory of Genetic Engineering, Department of Genetics, Fudan University School of Life Science, Shanghai 200433, China
b Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Received: 12 September 2014; Revised: 18 December 2014; Accepted: 21 December 2014; Available online: 5 January 2015
ABSTRACT
The study of the diversity of regenerative potential across metazoan phylogeny poses fundamental challenges in biology. Invertebrates such as Hydra and planarians exhibit remarkable regenerative abilities, allowing them to regenerate entire organisms from small body segments. Similarly, vertebrates like teleost fish and amphibians can regenerate extensive body sections. However, this regenerative capacity is significantly reduced in mammals, although certain major organs retain regenerative capabilities. Common strategies underlying various regeneration processes include the activation of adult stem cells and proliferation of differentiated cells. This review discusses the cellular features and molecular mechanisms of regeneration in model organisms, including Hydra, planarians, zebrafish, newts, and several mammalian organs.
KEYWORDS: Regeneration; Stem cells; Dedifferentiation; Model organisms; Mammalian organs; Tissue repair
INTRODUCTION
Regeneration is a widespread biological phenomenon across the animal kingdom, exhibiting varied capabilities from invertebrates to humans. Organisms like Hydra, planaria, and starfish can remarkably regenerate entire individuals from small body fragments. On the other hand, groups such as birds, nematodes, and leeches have nearly lost this capability (Bely and Nyberg, 2010).
At the tissue or organ level, nearly all species can regenerate damaged tissues, although the methods of regeneration differ significantly among tissues and species (Bely and Nyberg, 2010). For basal metazoans, such as sponges (Phylum Porifera), regeneration involves employing totipotent stem cells known as archeocytes. In contrast, several vertebrates utilize lineage-restricted progenitors in various tissues.
Diverse cellular modes of regeneration and their distribution among taxonomic groups are informative areas of research. Regeneration processes are typically classified into two modalities: morphallaxis, which involves the redeployment of existing cells without active proliferation, and epimorphosis, which involves cell proliferation and the formation of a blastema (Tanaka and Reddien, 2011).
Despite significant understanding of regeneration in select model organisms, numerous fundamental questions remain. For instance:
How many distinct forms of regeneration exist?
What type of cellular features and mechanisms are present during regeneration?
Are there common molecular pathways across different regeneration types?
This review examines broad patterns of regenerative ability across metazoan phylogeny, emphasizing model organisms including Hydra, planarians, zebrafish, and newts, as well as various mammalian organs.
REGENERATION IN MODEL ORGANISMS
Hydra
Organisms like jellyfish, sea anemones, corals, and specifically, Hydra, fall under the phylum Cnidaria, which is a sister phylum to Bilateria. Freshwater polyps exhibit tubular, radially symmetric bodies and have been a focus of regenerative studies since the discovery by Swiss researcher Abraham Trembley in 1744, noting their ability to completely regenerate their heads post-amputation (Lenhoff et al., 1986). This astonishing regenerative ability inspired the naming of Hydra after a Greek mythological monster capable of regrowing heads.
Hydra can regenerate entire polyps from tiny body fragments. Even dissociated Hydra cells can reaggregate, reestablish polarity, and produce a new polyp (Gierer et al., 1972). As diploblast organisms, Hydra utilize three lineage-restricted types of stem cells to regenerate all tissues. These are:
Ectodermal epithelial cells
Endodermal epithelial cells
Interstitial cells (i-cells) - multipotent stem cells from the ectoderm that can differentiate into neurons, gland cells, nematocytes, and gametes (David and Murphy, 1977).
Hydra employs morphallactic regeneration (morphallaxis), which is characterized by tissue morphogenesis using existing cells without new cell production (Cummings and Bode, 1984). For example, following head removal, regeneration occurs without detectable cell proliferation. Instead, gastric column cells are stimulated by injury to differentiate into replacement head cells (Chera et al., 2009).
Hydra experiences a phenomenon called apoptosis-induced compensatory proliferation (Fig. 1B). Upon mid-gastric transection, a burst of apoptosis occurs at the head-regenerating fragment's ends, while the foot-regeneration fragment exhibits no apoptotic response. Apoptotic i-cells secrete Wnt3, inducing a proliferation zone in neighboring cells below the apoptosis site (Chera et al., 2009). Thus, apoptosis is both necessary and sufficient to trigger head regeneration in Hydra.
Activation patterns in Hydra vary depending on amputation level, where β-catenin activation via Wnt3 suggests differential responses in cell remodeling (Chera et al., 2009).
Planarians
Planarians, a form of flatworm, were first reported to possess exceptional regenerative capabilities by Peter Simon Pallas in 1778. These organisms can regenerate any missing body part and replace aging differentiated cells, maintaining adult tissues. Morgan (1898) demonstrated that regeneration in planarians involves both morphallaxis and epimorphosis, where the latter includes blastema formation.
Blastema formation is reliant on somatic stem cells, or neoblasts, distributed throughout the planarian body, except in specific regions (Tanaka and Reddien, 2011). Although evidence indicates that neoblasts are pluripotent, their heterogeneous gene expression raises the debate about their status as either a single cell type or various lineage-restricted progenitors (Hayashi et al., 2010).
Planarians have been subjected to numerous experiments examining the potential of individual dividing cells. Wagner et al. (2011) demonstrated that single clonogenic neoblasts can regenerate nearly all known post-mitotic cell types across germ layers. Remarkably, a single asexual neoblast can regenerate a lethally irradiated host's body, turning it into a genetic clone of the donor (Wagner et al., 2011). Species like Dugesia japonica effectively regenerate all body parts, while others, such as Phagocata kawakatsui, are only capable of limited regeneration, indicating variations in regenerative capacity (Liu et al., 2013).
Subsequent studies have identified two specific defects in the regenerative processes of Dendrocoelum lacteum, which can only regrow heads from tail fragments post-amputation:
Failure to establish anterior (head) identity
Improperly retained tail identity
These findings highlight the role of Wnt signaling in maintaining blastema fate specification during regeneration and suggest a correlation between Wnt/b-catenin signaling and regeneration abilities in planarians (Liu et al., 2013).
Zebrafish
Zebrafish serve as a vital genetic model for vertebrate tissue regeneration, known for their remarkable ability to regenerate structures across various body parts, including appendages and internal organs such as the cardiovascular system and central nervous system. After caudal fin amputation, the epidermis rapidly covers the wound, fibroblasts and osteoblasts migrate and reorganize to form a blastema—a source of new fin structures. In contrast to planarian neoblasts, blastema formation in zebrafish occurs through dedifferentiation (Knopf et al., 2011).
Following fin amputation, osteoblasts down-regulate bone differentiation markers and form a regeneration blastema. Similarly, activation of the Wnt/b-catenin and Activin-bA pathways is crucial for successful blastema formation and outgrowth (Jazwinska et al., 2007; Whitehead et al., 2005).
Regeneration processes in zebrafish also feature distinct cell death phases essential to activating regenerative mechanisms (Gauron et al., 2013).
Zebrafish can also regenerate heart tissue post-injury, with cardiomyocytes showcasing remarkable regenerative capabilities. The heart can renew itself, demonstrating the efficacy of cascades like FGF, RA, and PDGF signaling for cardiac repair (Poss et al., 2002). Recent studies highlight the pivotal roles of existing cardiomyocytes in heart regeneration (Senyo et al., 2013).
Amphibians
Urodele amphibians, like newts and axolotls, demonstrate extraordinary regenerative abilities by regrowing limbs, tails, and portions of the heart and brain. Limb regeneration proceeds through a series of stages, including wound healing via the formation of an apical epidermal cap and subsequent blastema formation, whereby progenitor and dedifferentiated muscle cells regenerate the lost limb (Whited and Tabin, 2009).
Studies indicate that during limb regeneration in amphibians, existing muscle fibers dedifferentiate to contribute to new muscle fiber formation (Lo et al., 1993). Several molecular pathways crucial for limb regeneration include Wnt/b-catenin and Hedgehog signaling pathways (Kawakami et al., 2006; Yokoyama et al., 2007).
Furthermore, urodele amphibians exhibit unique lens regeneration capabilities; following lentectomy, epithelial cells from the iris can transdifferentiate into lens cells (Tsonis et al., 2004).
Mammalian Organs
The regenerative capacities within mammalian tissues and organs vary significantly. While not as pronounced as those in amphibians, mammals can regenerate specific tissues such as skin, bone, liver, and pancreas due to the presence of multipotent stem cells in the respective tissues.
Pancreas:
In mammals, pancreatic β-cells undergo turnover primarily during early life stages, with significant mass expansion observed during pregnancy or obesity. Mechanisms for β-cell regeneration include replication of existing β-cells or differentiation from pancreatic progenitors (neogenesis). Studies indicate that β-cell generation predominantly occurs from pre-existing cells (Dor et al., 2004).
Heart:
In adult mammals, cardiac regenerative capacity is limited. Nonetheless, research showcases that under injury conditions, pre-existing cardiomyocytes can partially regenerate function (Senyo et al., 2013). Pathways like Wnt and microRNA involvement have emerged as conducive to enhancing cardiomyocyte proliferation (Eulalio et al., 2012).
PERSPECTIVES
The understanding of tissue regeneration has progressed with recent revelations regarding stem cell plasticity and the roles of dedifferentiation. Recovery mechanisms diversify depending on injury type and extent, encompassing cell division, stem cell activation, dedifferentiation, and transdifferentiation. The involvement of various pathways across species highlights the potential for designing therapeutic regenerative strategies.
Acknowledgments
The authors thank their colleagues for input on the manuscript and acknowledge funding support received from several grants.
References
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