Birth Defects Research (Part C) 84:265–280 (2008) REVIEW Mammalian Regeneration and Regenerative Medicine Ken Muneoka,* Christopher H. Allan, Xiaodong Yang, Jangwoo Lee, and Manjong Han Mammals are generally considered to be poor regenerators, yet there are is driven by (1) the potential of a handful of mammalian models that display a robust ability to regener- adult stem cells to participate in ate. One such system is the regenerating tips of digits in both humans the formation of various organ and mice. In vitro studies of regenerating fetal human and mouse digit systems when introduced in early tips display both anatomical and molecular similarities, indicating that the embryos (Jiang et al., 2002), (2) mouse digit is a clinically relevant model. At the same time, genetic stud- the feasibility of transforming ies on mouse digit tip regeneration have identified signaling pathways required for the regeneration response that parallel those known to be adult cells into pluripotent stem important for regeneration in lower vertebrates. In addition, recent stud- cells (Yamanaka, 2008), and (3) ies establish that digit tip regeneration involves the formation of a blas- the isolation and characterization tema that shares similarities with the amphibian blastema, thus estab- of adult multipotent stem cells lishing a conceptual bridge between clinical application and basic research from virtually every tissue of the in regeneration. In this review we discuss how the study of endogenous body (Crisan et al., 2008). The regenerating mammalian systems is enhancing our understanding of second approach involves a bioen- regenerative mechanisms and helping to shed light on the development gineering strategy in which a sub- of therapeutic strategies in regenerative medicine. Birth Defects strate or scaffold is introduced Research (Part C) 84:265–280, 2008. VC 2008 Wiley-Liss, Inc. that can either be infiltrated by host cells (Badylak, 2007), or Key words: regeneration; mammal; digit; finger; blastema; ossification seeded with selected cells before implantation (Howard et al., INTRODUCTION and on the body’s endogenous 2008). This approach includes the In this posthuman genome/post- ability to repair wounds following in vitro engineering of specific tis- animal cloning era of modern biol- injury on the other. The goal of re- sues for use in transplantations, ogy, many have turned their generative medicine is to be able and in doing so sidesteps the attention to the prospect of con- to replace adult body parts on problems associated with tissue trolling the regeneration of tissues demand, and to this end we can morphogenesis and patterning or organs that do not regenerate identify three general avenues that are key to the successful in humans. Successes in this new being taken for the development regeneration of injured body field of Regenerative Medicine of novel regeneration therapies. parts. However, it does introduce would have enormous impact on The first is a cell based approach. a secondary problem of integrat- current medical practices and, as This approach has grown largely ing an engineered tissue with the well, on the general quality of from the successes in the use of host that still needs to be human life. Regenerative medicine hematopoietic stem cells in cell addressed (Khan et al., 2008). is strongly influenced by break- replacement therapies for the cure The third approach is to study throughs in our understanding of of blood diseases (Bhattacharya naturally regenerating models for organ and tissue formation during et al., 2008). The potential to comparison with nonregenerating embryogenesis on the one hand, expand into other organ systems injury wounds to discover critical Ken Muneoka is from Division of Developmental Biology, Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana and The Center for Bioenvironmental Research, Tulane University, New Orleans, Louisiana. Christopher H. Allan is from Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington. Xiaodong Yang, Jangwoo Lee, and Manjong Han are from Division of Developmental Biology, Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana. Grant sponsor: National Institutes of Health; Grant numbers: R01-HD043277; P01-HD022610 *Correspondence to: Ken Muneoka, Division of Developmental Biology, Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118. E-mail: [email protected] Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/bdrc.20137 VC 2008 Wiley-Liss, Inc. 266 MUNEOKA ET AL. factors necessary for a regenera- with a focus on limb or tail regen- ofablastemathatmediatesthe tion response, and this is the pri- eration in adult urodeles (Brockes regeneration response. mary topic of this review. This and Kumar, 2005; Tanaka, 2003) approach represents a long history or larval anurans (Slack et al., EARS AND DEERS of experimental inquiry focused 2008). While mammals lack simi- largely on invertebrate models that lar regenerative capabilities, there The ears of some mammals are have enhanced regenerative ability are a handful of model systems in able to undergo scar-free healing (Sanchez Alvarado and Tsonis, which a variation of appendage and regeneration after an exci- 2006) and selected vertebrate regeneration has been described, sional hole punch that removes a groups that possess the ability to and these models provide a cylindrical mass of tissue including regenerate structures such as the glimpse at the limitations and epidermis, dermis, muscle and limb and tail (Brockes and Kumar, potential for regeneration in cartilage. This response in mam- 2005; Gardiner, 2005). Included in humans. These include the closure mals was first characterized in this category are studies on the of excisional tissues in ears rabbit ears and later shown to be developing appendages of mam- following hole punch in rabbits a characteristic not restricted to mals, birds, and frogs which pos- and mice (Metcalfe et al., 2006), lagomorphs (Williams-Boyce and sess regenerative ability that is lost the annual regeneration of antlers Daniel, 1986). In recent years as the animal matures (Muller in deer (Price et al., 2005; Kier- research on ear hole punch regen- et al., 1999). Although the leap dorf et al., 2007), and the regen- eration has been stimulated by the between regenerating systems and eration of amputated digit tips finding that different mouse human therapies may seem large, known to occur in humans and strains display variability in this there is substantial evidence that rodents (Han et al., 2005). regeneration response (Clark signaling pathways important for Although the regenerative capa- et al., 1998; Kench et al., 1999; regeneration have been conserved bility of mammals does not com- Li et al., 2001), raising the possi- through evolution (Sanchez Alvar- pare with that of amphibians, it is bility that the genetic basis of this ado, 2000; Brockes et al., 2001), critical to keep in mind that these variation might be uncovered and there are examples of specific mammalian models provide (Heber-Katz, 1999). In mice, a 2- signaling pathways or genes that insight into how successful regen- mm diameter hole punch under- are important for regeneration in eration can be accomplished goes re-epithelization that in- both traditionally regenerating and within the context of a warm- volves epidermal closure from the nonregenerating organisms (Taylor blooded terrestrial animal with two opposite surfaces of the ear, et al., 1994; Yokoyama et al., similarities to humans. Lessons and centripetal filling in of the hole 2000; Beck et al., 2003; Han et al., learned from such examples are is driven by growth of a blastema- 2003). In addition, there are a likely to provide important insight like structure that forms between handful of mammalian systems into how to effectively modify the the existing ear tissue and the that can successfully regenerate. human wound environment to wound epidermis. The MRL strain, Studies of these systems are pro- elicit an enhanced regenerative also known as the healer strain, ducing important insight into the response, or to establish a func- displays the highest level of regen- feasibility of an enhanced endoge- tional interface with a bioengi- erative ability described (Heber- nous regenerative response in neered or artificial organ or struc- Katz, 1999); however, even in this humans, and also in the design of ture. The mammalian ear punch strain complete regeneration does alternative strategies in regenera- and the deer antler models have not always occur (Rajnoch et al., tive medicine, particularly to recently been reviewed (Price 2003). The regeneration process is address the problem of integration et al., 2005; Metcalfe et al., characterized by a wound healing with host tissues (see Pendegrass 2006; Kierdorf et al., 2007), so a response that involves formation et al., 2006). In this review we very brief introductory overview of a specialized wound epidermis highlight studies on appendage is provided here and the reader is that integrates the epidermal regeneration in mammals, with directed to these excellent re- layers from the inner and outer particular emphasis on the regen- views. We will focus most of our ear surfaces. This wound healing erating digit tip, in the context of attention on the human and response is influenced by the na- how such efforts may impact the mouse digit models that we have ture of the injury