Appendage Regeneration

Jo Ann Cameron, PhD
Ellen A.G. Chernoff, PhD
Michael W. King, PhD
Anthony L. Mescher, PhD
Anton W. Neff, PhD
Rosamund C. Smith, PhD
Fengyu Song, DDS, MS, PhD
David L. Stocum, PhD

Jo Ann Cameron, PhD, Affiliate Faculty

Positions

• Associate Professor, Department of Cell and Developmental Biology and College of Medicine
• Core Faculty Member, Regenerative Biology and Tissue Engineering
• Regeneration Research Theme, Institute for Genomic Biology, University of Illinois at Urbana-Champaign

Address
Institute for Genomic Biology
Room 2103
1206 West Gregory Drive, Urbana, IL 61801

Phone: (217) 333-1254
Fax: (217) 244-1800
Email: joanncam@uiuc.edu

Research Interests

We are conducting studies that will provide insight into why most adult vertebrates, including humans, lose the ability to regenerate their limbs. The same principles that apply to developing systems often hold true for regenerating systems. Our laboratory has a long-standing interest in how vertebrate limb pattern is established during development and regeneration. Successful vertebrate limb regeneration is accomplished by formation, continued growth, patterning, and differentiation of a regeneration blastema at the cut surface of a limb stump. Mature tissues adjacent to the amputation surface lose their extracellular matrix and cells re-enter the cell cycle in preparation for stump repair and regeneration of lost parts. At the cellular level a regeneration blastema resembles the original embryonic limb bud that gives rise to the mature limb. Presently, we are examining initial cellular and molecular events in the stump following partial hindlimb amputation in pre-metamorphic and metamorphic Xenopus laevis (African Clawed Frog). Pre-metamorphic tadpoles can regenerate hindlimb parts, while the ability to regenerate declines as the tadpole undergoes metamorphosis. Tadpole hindlimb regeneration provides a natural loss-of-function system that resembles the typical loss of ability to regenerate in vertebrates. We are studying cellular and molecular features of blastemas at the developmental stages and amputation levels where there is predictably “good regeneration” and where there is predictably “poor” regeneration. Blastemas with characteristics most closely resembling limb buds are more likely to regenerate successfully. One hypothesis we are investigating is that the cellular and molecular features of “good” and “poor” blastemas can be used to predict whether a particular blastema will regenerate more or less completely. From our work and the work of other investigators we know that many of the same genes important during embryonic limb development are expressed again during limb regeneration. Patterning factors like sonic hedgehog, Hox genes and Msx, and growth factors like Fgfs are expressed during limb regeneration. Expression of these genes provides cell-signaling centers within limb buds at each developmental stage and similar centers within regeneration blastemas during regeneration. Particular genes may not be expressed or their expression pattern may change when regeneration fail.

Recent Publications

• Wolfe, A, Nye, HDL and Cameron, JA. 2000. Extent of ossification at the amputation plane is correlated with the decline of blastema formation and regeneration in Xenopus Laevis hindlimbs. Dev. Dynamics, 218:681-697.
• Chernoff EAG, Stocum DL, Nye HLD, Cameron JA. 2003. Urodele spinal cord regeneration and related processes. Dev. Dynamics 226:295-307.
• Nye HLD, Cameron JA, Chernoff EAG, Stocum DL. 2003. Regeneration of the urodele limb: a review. Dev. Dynamics 226:280-294.
• Wolfe AD, Crimmins G, Cameron, JA, Henry JJ. 2004. Early Regeneration Genes: Building a Molecular Profile for Shared Expression in Cornea-Lens Transdifferentiation and Hind Limb Regeneration in Xenopus laevis. Dev. Dynamics, 230: 615-629.
• Nye, HLD, Cameron JA. 2005. Strategies to Reduce Variation in Xenopus laevis Regeneration Studies. Dev. Dynamics. 234:151-158

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Ellen A.G. Chernoff, PhD

Positions

• Associate Professor of Biology
• Adjunct faculty, Stark Institute for Neuroscience

Address
Dept. of Biology, School of Science
Indiana University-Purdue University Indianapolis
723 W. Michigan St.
Indianapolis, IN 46202-5132

Phone: (317) 274-0591
Fax: (317) 274-2846
Email: echernof@iupui.edu

Research Interests

My laboratory studies amphibian spinal cord and limb regeneration. We examine spinal cord and limb regeneration using the frog Xenopus laevis, and a salamander, the axolotl (Ambystoma mexicanum). Projects include characterizing the stem cell properties of spinal cord and expression of dorsoventral patterning genes in regeneration. We also study the involvement of stem cells in amphibian limb regeneration as an alternative to the involvement of dedifferentiation in this process. We are comparing differences at different stages of the life cycle. Frog tadpoles lose their ability to regenerate as they approach metamorphosis, and we compare regenerating and non-regenerating tissue. Salamanders regenerate even as adults, so we can compare regeneration in larval, juvenile and adult animals. Lastly, we are comparing the role of stem cells in regeneration between normal axolotls and the mutant short-toes (s/s) which can regenerate spinal cord and tail, but not limbs.

Recent Publications

• Chernoff EAG, Sato K, Corn A and Karcavich RE (2002) Spinal Cord Regeneration: Intrinsic Properties and Emerging Mechanisms. Sem Cell Develop Biol 13:361-368
• Nye HL, Cameron J, Chernoff EAG and Stocum DL. (2003) Regeneration of the Urodele Limb: A Review. Develop. Dyn. 226:280-294.
• Nye HLD, Cameron, J., Chernoff EAG and Stocum DL (2003) Extending theTable of Stages of Normal Development of the Axolotl: Limb Development. Devel Dyn 226:555-560 (Cover picture).
• Showalter AD, Yaden BC, Chernoff EAG and Rhodes SJ (2003) Cloning and Analysis of Axolotl ISL2 and LHX2 LIM-Homeodomain Transcription Factors. Genesis (Developmental Genetics) 38:110-121.
• Johnson CD, Narasimha Chary S, Chernoff EA, Zeng Q, Running MP, Crowell DN. (2005) Protein Geranylgeranyltransferase I Is Involved in Specific Aspects of Abscisic Acid and Auxin Signaling in Arabidopsis. Plant Physiol. 139:722-733.

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Michael W. King, PhD

Position

• Professor

Address
Indiana University School of Medicine Terre Haute
Center for Regenerative Biology and Medicine
Room 135HH
Terre Haute, IN. 47809

Phone: (812) 237-3417
Fax: (812) 237-7646
E-mail: miking@iupui.edu

Research Interests

Research being conducted in Dr. King's laboratory involves the isolation and characterization of novel proteins whose functions may regulate tissue regeneration. We are using the frog Xenopus laevis as a model. In this species limbs regenerate well during larval stages, but gradually lose this ability as the animal approaches metamorphosis. Adult frogs do not regenerate and the response of these structures to surgical transection is normally similar to that of higher vertebrates (i.e. scarring). This stage difference in regenerative ability can be used to advantage experimentally to discover, by differential gene screening, the molecules and molecular pathways that drive regeneration or inhibit regeneration within the same species. Long-term goals of this research are to identify mechanisms by which control over regeneration regulating genes can be exerted. The aim is that by manipulating these genes in humans we will be able to stimulate tissue repair and regeneration.

Recent Publications

• Alshaibi, N, King, MW, Duong, T, and Ghosh, SK 2007 DP58, an inducible myeloid protein, is constitutively expressed in murine neuronal nuclei. Frontiers of Bioscience 12:2947-295
• Grow, MW, Neff, AW, Mescher, AL and King, MW 2006 Global analysis of gene expression in Xenopus hindlimbs during stage-dependent complete and incomplete regeneration. Dev. Dyn. 235:2667-2685
• Neff, AW, King, MW, Harty, MW, Nguyen, T, Calley, J, Smith, RC and Mescher, AL, 2005 Expression of Xenopus XlSALL4 during limb development and regeneration. Dev. Dyn. 233:356-367
• Harty, M, Neff, AW, King, MW, and Mescher, AL 2003 Regeneration or Scarring: An Immunological Perspective. Dev. Dyn. 226: 268-279
• King, MW, Nguyen, T, Calley, J, Harty, MW, Muzinich, MC, Mescher, AL, Chalfant, C, N'Cho, M, McLeaster, K, McEntire, J, Stocum, D, Smith, RC, Neff, AW 2003 Identification of genes expressed during Xenopus laevis limb regeneration using subtractive hybridization. Dev. Dyn. 226: 398-409

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Anthony L. Mescher, PhD

Position

• Professor

Address
Medical Sciences Program
Jordan Hall 202
Indiana University Bloomington
Bloomington, IN 47405

Phone: (812) 855-4693
Fax: (812) 855-4436
Email: mescher@indiana.edu

Research Interests

Current research in the Mescher lab involves the interface between the inflammatory effects of amputation injury and the molecular events leading to epimorphic regeneration of amphibian limbs. Specifically, we are studying (1) the nature of genes expressed in the early post-amputation period in regenerating hindlimbs of larval frogs, with particular interest in genes related to inflammation, immunity, and dedifferentiation, (2) differences in expression of such genes between young larvae which regenerate limbs completely and older larvae with defective regeneration, in an attempt to elucidate the ontogenic loss of regenerative capacity, and (3) expression patterns and control of genes with an apparent role in both dedifferentiation and limb patterning. Dr. Mescher also maintains strong interest in the molecular basis of both the apical epithelial effect and the nerves’ trophic effect on blastema cell proliferation, which are required for epimorphic regeneration but remain incompletely understood.

Recent Publications

• AL. Mescher, W L. Wolf, E., A. Moseman, B. Hartman, C. Harrison, E. Nguyen, and AW. Neff (2007) Cells of cutaneous immunity in Xenopus: Studies during larval development. Dev Comp Immunol (in press)
• Grow MW, Neff AW, Mescher AL, King MW. (2006) Global analysis of gene expression in Xenopus limbs during stage-dependent complete and incomplete regeneration. Dev Dyn 235:2667-2685.
• Mescher AL, Neff AW (2005). Regenerative capacity and the developing immune system. Adv Bioch Eng/ Biotech 93:39-66.
• Neff AW, King MW, Harty MW, Nguyen T, Calley J, Smith RC, Mescher AL. (2005) Expression of Xenopus XlSALL4 during limb development and regeneration. Dev Dyn 233(2):356-367.
• Harty, M, AW Neff, MW King, and AL Mescher (2003) Regeneration or scarring: An immunologic perspective. Dev Dyn 226:268-279

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Anton W. Neff, PhD

Position

• Professor

Address
Medical Sciences Program
Jordan Hall 202
Indiana University Bloomington
Bloomington, IN 47405

Phone: (812) 855-7055
Fax: (812) 855-4436
Email: neff@indiana.edu

Research Interests

The Neff lab is interested in the molecular and cellular interactions required for tissue and organ regeneration utilizing amphibian model systems. Current work involves differential genomics and proteomics to identify limb regeneration regulatory pathways with emphasis on immunomodulatory and stem cell establishment/maintenance pathways.

Recent Publications

• Harty, M., A.W. Neff, M.W. King, and A.L. Mescher (2003) Regeneration or scarring: An immunologic perspective. Dev. Dyn 226:268-279
• King, M.W., T. Nguyen, J. Calley, M.W. Harty, M.C. Muzinich, A.L. Mescher, C. Chalfant, M. N’Cho, K. McLeaster, J. McEntire, D. Stocum, R.C. Smith, and A.W. Neff. (2003) Identification of genes expressed during Xenopus laevis limb regeneration by using subtractive hybridization. Dev. Dyn 226:398-409
• Mescher AL, Neff AW (2005). Regenerative capacity and the developing immune system. Adv. Biochemical Engineering/ Biotechnology 93:39-66.
• Neff AW, King MW, Harty MW, Nguyen T, Calley J, Smith RC, Mescher AL. (2005) Expression of Xenopus XlSALL4 during limb development and regeneration. Dev Dyn. 233(2):356-367.
• Grow MW, Neff AW, Mescher AL, King MW. (2006) Global analysis of gene expression in Xenopus limbs during stage-dependent complete and incomplete regeneration. Dev. Dyn. 235:2667-2685.
• AL. Mescher, W L. Wolf, E., A. Moseman, B. Hartman, C. Harrison, E. Nguyen, and AW. Neff (2006) Cells of cutaneous immunity in Xenopus: Studies during larval development. Developmental and Comparative Immunology (Epub ahead of print).

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Rosamund C. Smith, PhD

Positions

• Research Advisor, Biotechnology Discovery Research
• Adjunct Professor, Dept. of Biology, IUPUI

Address
Lilly Research Laboratories DC 0434
Lilly Corporate Center
Indianapolis, IN 46285

Phone: (317) 277-5229
Fax: (317) 277-2934
Email: smith_ros@lilly.com

Research Interests

My research group is part of the Biotechnology Discovery Research division of Lilly Research Laboratories, a division of Eli Lilly and Company. Our goal is to develop new pharmaceuticals for the treatment of human disease. I am particularly interested in developing novel therapies that will aid human tissue regeneration and repair. We (in collaboration with the IU Center for Regenerative Biology and Medicine, Indianapolis, IN, USA) have used the frog Xenopus laevis to identify genes that are involved in limb regeneration. A number of these genes have mammalian homologues and we are currently exploring the role and potential therapeutic utility of these genes in mammalian tissue repair.

Recent Publications

• Smith R.C. and Rhodes S. (2000) Applications of developmental biology to medicine and animal agriculture. Progress in Drug Research 54, 214-256.
• Chernoff E.A.G., Clarke D.O., Wallace-Evers. J.L., Hungate-Muegge L.P. and R.C. Smith (2001) The effect of collagen synthesis inhibitory drugs on somitogenesis and myogenin expression in cultured chick and mouse embryos. Tissue and Cell, 33, 97-110.
• Krishnan P., King M.W., Neff A.W., Sandusky G.E., Bierman K.L., Grinnell B., and Smith R.C. (2001). Human truncated Smad 6 (Smad6s) inhibits the BMP pathway in Xenopus laevis. Develop. Growth Differ. 43, 115-132.
• King M.W., Nguyen T., Calley J., Harty M.W., Muzinich M.C., Mescher A.L., Chalfant C., N’Cho M., McLeaster K., McEntire J., Stocum D., Smith R.C. and Neff A. W. (2003) Identification of genes expressed during Xenopus laevis limb regeneration by using subtractive hybridization. Dev. Dynamics 226, 398-409
• Neff A.W., King M.W., Harty M.W., Nguyen T., Calley J., Smith R.C. .and Mescher A.L. (2005) Expression of Xenopus XlSALL4 during limb development and regeneration. Dev. Dynamics 233, 356-367.

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Fengyu Song, DDS, MS, PhD

Position

• Assistant Professor

Address
Indiana University School of Dentistry
Department of Oral Biology
1121 W. Michigan Street, Room 244
Indianapolis, Indiana 46202

Phone: (317) 274-2415
Fax: (317) 278-1411
Email: fesong@iupui.edu

Research Interests

The research in my laboratory has been focused on the extracellular matrix (ECM) turnover in healthy and diseased tissues, and in the tissue regeneration process. ECM proteinases, including serine proteinases, cystein proteinases, and a group of zinc-dependent endopeptidases known as the matrix metalloproteinases (MMPs), collectively are capable of cleaving most of the major components of the ECM and are believed to be some of the tools by which cells facilitate the ECM remodeling during the degeneration and regeneration process. Specifically we are examining:

• The roles of the serine proteinases and MMPs in the degenerative joint diseases including temporamandibular joint disorder, osteoarthritis, and rheumatoid arthritis to seek the potential marker(s) for disease diagnosis and treatment;
• The roles of MMPs in amphibian limb regeneration using regeneration capable and incapable animal models such as the frog Xenopus laevis, and the axolotl, Ambystoma mexicanum; and
• The induction of the regenerative ability of adult stem cells, including pulp stem cells and gingival fibroblasts, in order to restore the abilities of these cells to regenerate the tooth, the gingival soft tissue and the periodontal bone.

Recent Publications

• Song F, Windsor LJ (2005) Novel non-matrix metalloproteinase mediated collagen degradation. Biochimica et Biophysica Acta (BBA) - General Subjects, 1721(1): 65-72.
• Song F, Wisithprom K, Zhou J, Windsor LJ (2006) Matrix metalloproteinase dependent and independent collagen degradation. Frontiers in Bioscience, 11:3100-20.
• Song F, Bergdoll AS, Windsor LJ (2006) Temporomandibular joint synovial fibroblasts mediate serine proteinase dependent Type I collagen degradation. Biochimica et Biophysica Acta (BBA) - General Subjects, 1760 (10): 1521-1528.
• Ellis M, Song F, Parks ET, Eckert G, Dean J, Windsor LJ (2007) An Evaluation of Toothprints®: DNA yield, quality, and bite registration. J Am Dent Assoc, 138(9):1234-1240.

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David L. Stocum, PhD

Positions

• Professor of Biology
• Director, Indiana University Center for Regenerative Biology and Medicine
• Research Scholar, Institute for Genomic Biology, University of Illinois at Urbana-Champaign

Address
Department of Biology, School of Science
Indiana University-Purdue University Indianapolis
723 W. Michigan St.
Indianapolis, IN 46204

Phone: (317) 274-0627
Fax: (317) 274-2846
Email: dstocum@iupui.edu

Research Interests

Research in my laboratory has three foci. The first is the cellular and molecular analysis of how the amphibian limb regeneration blastema self-organizes the patterning of amputated limb segments in the proximodistal axis. The second is proteomic analysis of the molecular differences that differentiate the regeneration-competent limbs of salamanders and early frog tadpoles from the regeneration-deficient limbs of metamorphosed froglets. The third is the use of regeneration templates that mimic the ECM, as well as signaling molecules, of regeneration-competent limbs, to investigate ways to promote the regeneration of regeneration-deficient froglet limbs and mouse digits. In addition, I write articles and books that synthesize and promote the rapidly emerging field of regenerative biology and medicine.

Recent Publications

• Stocum DL (2003) Stem cells in amphibian regeneration. In: Stem Cell Handbook. Sell S, ed. Humana Press, Towota, NJ, pp 89-100.
• Stocum DL (2004) Amphibian regeneration and stem cells. In Regeneration: Beyond the Stem Cells. Heber-Katz E (ed). Springer Verlag, Heidelberg, pp 1-70.
• Stocum DL (2004) Tissue Restoration Through Regenerative Biology and Medicine. Adv in Anat, Embryol and Cell Biol 176:1-104.
• Stocum DL (2005) Stem cells in CNS and cardiac regeneration. In: Advances in Biochemical Engineering/Biotechnology: Regenerative Medicine. Yannas IV (ed). Springer-Verlag, pp 135-159.
• Stocum DL (2006) “Regenerative Biology and Medicine”. Academic Press, San Diego/Elsevier, New York, 435 pp.

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