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Tooth Transplantation in the Mouse I Tooth Transplantation in the Mouse I. THE USE OF PROCION DYES AND TRITIATED PROLINE IN A STUDY OF SYNGENEIC TOOTH GERM TRANSPLANTATION ' JAN KLEIN. WALTER R. SECOSKY2 AND DAGMAR KLEIN Departments of Oral Biology, Oral Surgery arid Human Genetics, The University of Michigari, Ann Arbor, Michigan 481 04 ABSTRACT Tooth germs of first molars from four- to six-day old mice were transplanted heterotopically into the connective tissue under the dorsal skin of adult syngeneic recipients. The fate of the transplants was studied by histologic staining, vital staining with procion dyes, and autoradiography. Together these methods provided the following picture of the development of the transplant. Ex- traction of the tooth germ severs its vascular connections and disturbs the nutri- tional environment of the tooth so that many cells undergo necrosis and degen- eration. The resulting inflammatory response clears the transplant of necrotic tissue, leaving a fibrous pulp of low cellularity and an extensively disrupted odontoblastic layer; the enamel organ is reduced to only a few epithelial cells. In the second week following transplantation, however, the surviving cells start to proliferate and the tissues of the transplant begin to reorganize. Reorganiza- tion starts at the apical foramen and spreads to the rest of the tooth. The central pulp is penetrated by new blood vessels, its cellular content is reestablished, and its morphology returns to normal. Odontoblasts start producing dentin which at first is highly irregular and contains many cells (osteodentin). Later the dentin formation becomes more and more regular and the dentin assumes its normal tubular structure. New enamel is not formed at any time after transplantation. The cells of the enamel organ undergo squamous metaplasia and form epithelial cysts. Abortive root formation is observed but typical roots never develop. Rudi- ments of periodontal ligament develop rarely. The transplants are enclosed in a capsule of connective tissue. It is concluded that the heterotopically transplanted tooth germs maintain their capability to recover, develop, and differentiate in syngeneic recipients. Al- though almost all of the developmental processes continue in the transplant after a period of adjustment, some of them are abortive. The literature on tooth transplantation technically. Between these two extremes is enormous. A bibliography compiled in lie various concepts, for example, host- 1962 (Ivhnyi, '62) lists over 300 publica- tissue acceptance of both syngeneic and tions, and since then some 300 more have allogeneic grafts (Haley and Costich, '69), appeared (Natiella et al., '70). Widely acceptance of syngeneic grafts and rejec- contrasting views on the antigenicity of tion of allografts (IvBnyi and Vacek, '64), teeth have been expressed. It has been re- rejection of some allografts and acceptance ported that tooth xenografts survive (Flem- of others according to the strength of the ming, '55; Cserepfalvi and Price, '68), histocompatibility barrier (IvAnyi, '68; which implies that the tooth tissues are f Supported by grant DE-02731 from the National non-antigenic. Other investigators, how- Institute for Dental Research, PHS. 2 Portions of this investigation are being submitted ever, have concluded that even syngeneic as partial fulfillment of the requirements for the Mas- grafts do not survive (Lefkowitz, '61) and ter of Science deeree in oral surgery, Horace H. Rack- ham School of Graduate Studies, Ann Arbor, Mich- that transplantation of teeth is not possible igan. AM. J. ANAT., 131: 371-386. 3 71 372 JAN KLEIN, WALTER R. SECOSKY AND DAGMAR KLEIN Weinreb et al., ’68), and induction of the transplant was prepared by making an transplantation immunity by allogeneic incision in the skin just behind the ears hard tissue (Shulman, ’64; Mincer and and opening a subcutaneous pouch by Jennings, ’70 ) and soft tissue of the tooth blunt dissection with iridectomy scissors. Zaleski et al.. ’67). The tooth germ was inserted as far into The confusion in the field of transplanta- the pouch as possible and the incision tion immunology stems from two main closed. The operation was performed under factors: first, the use of laboratory animals intraperitoneal Nembutal anesthesia (0.5 with nondescript genetic backgrounds, mg pentobarbital sodium per 10 gm body and second, the use of different criteria weight). The recipients were two- to three- for evaluating acceptance or rejection of month old mice. To avoid possible sex- the graft. In most studies the experimental linked histoincompatibility, only males subjects were “monkeys,” randomly bred were used. dogs. rabbits, guinea pigs, or rats. Only a Histologic eramination. At termination few investigators have used inbred strains, of the experiment, the transplanted teeth, and to our knowledge no one has used together with the surrounding tissue, were congenic resistant lines. As for evaluation dissected out and fixed in 4% paraform- methods, many of these have involved only aldehyde dissolved in 0.2 M phosphate buf- gross observation of the tooth graft; others fer, pH 7.4. After fixation for 24 to 36 have included histologic techniques, but hours, the specimens were decalcified with the histologic criteria for survival or de- chelating agents in dilute HC13 and em- struction of the tooth graft vary from one bedded in paraffin. Serial sections of 10 ,u report to another. thickness were cut and stained with The experiments described below were hematoxylin and eosin (H and E). undertaken to reexamine the role of genetic Grossly the transplant usually appeared and nongenetic factors in tooth trans- as a small bulge at the site of the opera- plantation. The subjects were mice with tion, at least in the first postoperative days. known genetic background, and the meth- Later, when the transplant was being sur- ods involved standard histologic techniques rounded by connective tissue, the bulge augmented by the use of procion dyes and usually disappeared but the tooth was still tritiated proline as markers for the study palpable. About 1% of the transplants of dentinogenesis in transplanted teeth. could not be found; they were probably lost The first set of experiments focused on the either by migration or by technical failure. morphologic characteristics of syngeneic In some instances the grafts were lost be- he tero topic transplants. cause of infection. Vital staining with procion dyes. The MATERIALS AND METHODS following dyes were tested for in vivo Mice. Mice used in this work were of toxicity and €or efficacy observed in mark- the highly inbred strain C57BL/lOScSn ing hard tissues of normal teeth: red (abbreviated to B10) and its congenic re- M-8BS, scarlet M-GS, orange M-GS, olive sistant lines BlO.BY, BlO.A, BlO.LPa, and green M-3CS, grey M-3GS, purple H-3RS, E10.129(21M). Breeding pairs were sup- and blue H-5GS.4 The dyes were dissolved plied by Dr. George D. Snell, The Jackson in distilled water and injected intraperi- Laboratory, Bar Harbor, Maine, and were toneally. Toxicity was evaluated by inject- maintained in our colony by brother-x-sister ing groups of five mice with the dye solu- matings. Skin grafts exchanged between tions in dosages ranging from 2 to 5 mg/lO individuals of the same line survived gm body weight (b.w.) and recording the permanently. deaths each day for one week (table 1). Transplantation of tooth germs. Maxil- Marked difference in tolerance to different lary or mandibular first molar germs of dyes was observed: procion orange M-GS four- to six-day old donors were carefully and scarlet M-GS were tolerated in doses dissected out with 25-gauge syringe needles up to 5 mg/lO gm b.w.; whereas procion under a dissecting microscope and trans- purple H-3RS had some lethal effect even planted into the dorsal connective tissue 1 The Rupp and Bowman Co , Hlghland Park. Mich- igan of‘ the recipient. The site for reception of 4 Colab Laboratories, Inc , Glenwood, Illino~s. TOOTH TRANSPLANTATION 373 TABLE 1 In viuo toxicity of different procion dyes ~ No. of mice dead at days Procion after injection dye Dose No. of mice mg/lO gm b.w. injected 12345 Red M-8BS 5 5 221-- 4 5 12000 3 5 1211- 2 5 00000 Scarlet M-GS 5 5 00000 4 5 00000 3 5 00000 2 5 00000 Purple H-3RS 5 5 32--- 4 5 5---- 3 5 131-- 2 5 02000 Orange M-GS 5 5 00000 4 5 10000 3 5 00000 2 5 00000 Olive green M3GS 5 5 30100 4 4 10000 3 5 00000 2 5 10000 Grey M-3GS 5 5 20000 4 5 11000 3 5 00000 2 5 00000 f Blue H-5GS 5 5 11111 4 5 10000 3 4 00000 2 4 00000 Mice were injected intraperitoneally with water solutions of the dyes. Dose range: 2 to 5 mg per 1Ogm of body weight. in the low dosage of 2 mg/lO gm b.w. The mercury lamp, a BG12 exciter filter, and efficacy of the procion dyes was evaluated Zeiss barrier filter inserts (47 and 50). by their capacity to reveal distinct incre- The seven tested dyes fell into three groups mental zones of growth in dentin of dc- according to their marking suitability. In calcified sections of normal teeth cut the first group, procion red M-8BS and at 7 to 10 p. Groups of three to five mice scarlet M-GS were considered the most one to three weeks old were injected suitable of those tested. Zones of dentin with the individual dyes at the highest non- stained with these two dyes were visible toxic dosage as determined in the previous under the standard microscope but only experiment. One week after the injection, as pale lines with poor contrast against the mice were sacrificed and their teeth ex- the background. For this reason standard tracted, fixed, decalcified, and sectioned.
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