The common marmoset (Callithrix jacchus) is increasingly attractive for use as a non-human primate animal model in biomedical research. It has a relatively high reproduction rate for a primate, making it potentially suitable for transgenic modification. Although several attempts have been made to produce non-human transgenic primates, transgene expression in the somatic tissues of live infants has not been demonstrated by objective analyses such as polymerase chain reaction with reverse transcription or western blots. Here we show that the injection of a self-inactivating lentiviral vector in sucrose solution into marmoset embryos results in transgenic common marmosets that expressed the transgene in several organs. Notably, we achieved germline transmission of the transgene, and the transgenic offspring developed normally. The successful creation of transgenic marmosets provides a new animal model for human disease that has the great advantage of a close genetic relationship with humans. This model will be valuable to many fields of biomedical research.

Recent studies have shown that delayed transplantation of neural stem/progenitor cells (NSPCs) into the injured spinal cord can promote functional recovery in adult rats. Preclinical studies using nonhuman primates, however, are necessary before NSPCs can be used in clinical trials to treat human patients with spinal cord injury (SCI). Cervical contusion SCIs were induced in 10 adult common marmosets using a stereotaxic device. Nine days after injury, in vitro-expanded human NSPCs were transplanted into the spinal cord of five randomly selected animals, and the other sham-operated control animals received culture medium alone. Motor functions were evaluated through measurements of bar grip power and spontaneous motor activity, and temporal changes in the intramedullary signals were monitored by magnetic resonance imaging. Eight weeks after transplantation, all animals were sacrificed. Histologic analysis revealed that the grafted human NSPCs survived and differentiated into neurons, astrocytes, and oligodendrocytes, and that the cavities were smaller than those in sham-operated control animals. The bar grip power and the spontaneous motor activity of the transplanted animals were significantly higher than those of sham-operated control animals. These findings show that NSPC transplantation was effective for SCI in primates and suggest that human NSPC transplantation could be a feasible treatment for human SCI.

Human uterine endometrium exhibits unique properties of cyclical regeneration and remodeling throughout reproductive life and also is subject to endometriosis through ectopic implantation of retrogradely shed endometrial fragments during menstruation. Here we show that functional endometrium can be regenerated from singly dispersed human endometrial cells transplanted beneath the kidney capsule of NOD/SCID/␥ c null immunodeficient mice. In addition to the endometrium-like structure, hormonedependent changes, including proliferation, differentiation, and tissue breakdown and shedding (menstruation), can be reproduced in the reconstructed endometrium, the blood to which is supplied predominantly by human vessels invading into the mouse kidney parenchyma. Furthermore, the hormone-dependent behavior of the endometrium regenerated from lentivirally engineered endometrial cells expressing a variant luciferase can be assessed noninvasively and quantitatively by in vivo bioluminescence imaging. These results indicate that singly dispersed endometrial cells have potential applications for tissue reconstitution, angiogenesis, and human-mouse chimeric vessel formation, providing implications for mechanisms underlying the physiological endometrial regeneration during the menstrual cycle and the establishment of endometriotic lesions. This animal system can be applied as the unique model of endometriosis or for other various types of neoplastic diseases with the capacity of noninvasive and real-time evaluation of the effect of therapeutic agents and gene targeting when the relevant cells are transplanted beneath the kidney capsule.animal model ͉ bioluminescence imaging ͉ endometriosis ͉ menstruation ͉ angiogenesis H uman endometrium lines the uterus and comprises luminal and glandular epithelial cells, stromal fibroblasts, vascular smooth muscle cells, endothelial cells, and immune competent cells. These cell components coordinately participate in the cyclical changes of human endometrium, including proliferation, differentiation, and tissue breakdown and shedding under the influence of estrogen and progesterone during the menstrual cycle. This unique system of cyclic tissue regeneration also depends on the cyclical growth and regression of the blood vessels that supply the endometrium (1). In addition, angiogenesis is deeply involved in the pathogenesis of endometriumderived disorders such as endometriosis (2). Endometriosis, one of the most common gynecological diseases, is characterized by the presence of functional endometrial-like tissue outside the uterine cavity. It is an estrogen-dependent disorder associated with substantial morbidity; however, the etiology and pathophysiology are not well elucidated (3). To study the physiology of normal endometrium and the pathogenesis of endometriosis, a variety of in vivo models using small animals has been developed by using the transplantation of autologous or heterologous endometrial cells/tissues or endometriotic tissues (4).In the present study, taking advantage of newly de...

In this study, we investigated the carcinogenic response of transgenic mice carrying the human prototype c-Ha-ras gene, namely Tg rasH2/CB6F1 mice, to various genotoxic carcinogens and compared it with that of control non-transgenic CB6F1 mice (non-Tg mice). The present studies were conducted as the first step in the evaluation of the Tg rasH2/CB6F1 mouse as a model for the rapid carcinogenicity testing system. Short-term (< or = 6 months) rapid carcinogenicity tests of various genotoxic carcinogens, 4-nitroquinoline-1-oxide, cyclophosphamide, N,N-diethylnitrosamine, N-methyl-N-nitrosourea, N-methyl-N'-nitro-N-nitrosoguanidine and methylazoxymethanol, revealed that Tg rasH2/CB6F1 mice are more susceptible to these genotoxic carcinogens than control non-Tg mice. Tg rasH2/CB6F1 mice developed tumors more rapidly compared with non-Tg mice. Malignant tumors were observed only in the carcinogen-treated Tg rasH2/CB6F1 mice, but not in non-Tg mice treated with the same carcinogens. Each carcinogen induced tumors in corresponding target tissues of the Tg rasH2/CB6F1 mice. Only a very few lung adenomas but no other tumors were seen as spontaneous tumors during the 6 months of carcinogenicity tests. These results demonstrate that more rapid onset and higher incidence of more malignant tumors can be expected with high probability after treatment with various genotoxic carcinogens in the Tg rasH2/CB6F1 mice than in control non-Tg mice. The Tg rasH2/CB6F1 mouse seems to be a promising candidate as an animal model for the development of a rapid carcinogenicity testing system.

We developed a model of spontaneously high human remn hypertensron m the rat by producing two transgemc strains, one for human angrotensmogen with the endogenous promoter and one for human renm with the endogenous promoter Neither transgemc strain was hypertensive These strains were then crossed, producing a double transgemc strain The double transgemc rats, both males and females, developed severe hypertension (mean systolic pressure, 200 mm Hg) and died after a mean of 55 days If untreated The rats had a human plasma rerun concentratton of 2692381 (+SD) ng angtotensm I (Ang I)/mL per hour, plasma renm actrvrty of 1772176 ng Ang I/mL per hour, rat angtotensmogen concentratron of 1 492 1 pg Ang I/mL, and human angtotensmogen concentration of 78239 pg Ang I/mL (n=49) Control rats had plasma remn actrvrty of 3 7t3.9 ng Ang I/mL per hour and rat angrotensmogen of 1 3220 16 /lg Ang I/mL Angrotensmogen transgene expression by RNase protectton assay was ubrqmtously present but most prominent m liver Renm transgene expression was htgh m kidney but absent m liver The rats featured severe cardiac hypertrophy, with mcreased cross section of cardromyocytes but little myocardtal fibrosts The kidneys showed atrophrc tubules, thickened vessel walls, and increased mterstttmm Both the angtotensm-converting enzyme mhtbttor hsmopnl and the specific human remn mhtbttor remrkrren lowered blood pressure to normal values Double transgemc mice have been developed that exhibit features quite similar to those described here, their gene expressions are stmtlar The spectfictty of rodent and human renm 1s stmrlarly documented Although many elegant physrologtcal studtes can now be done m mice, rats nevertheless offer flexrbdrty, partrcularly m terms of detailed cardiac and renal phystology and pharmacology We conclude that this double transgemc strain wtll facthtate srmultaneous mvesttgatton of genettc and pathophystologtcal aspects of remn-induced hypertension The fact that human renm can be studied m the rat IS a unique feature of this model (Hypertensron. 1997 When infused wrth hREN, this otherwrse normotensrve rat becomes severely hypertensive 1 Under the condrtton of chronic mfusron wrth hREN, the rat is smtable for study of hREN mhtbitors, whrch otherwrse have no effect in the rat.2 However, for study of the human renm-angrotensm system m the rat for perrods ranging from weeks to months, the mimpump mfuston model has maJor shortcommgs, making rt not suitable for studying mechanisms of cardiac hypertrophy, hypertensive nephrosclerosrs, or central nervous system damage To ctrcumvent this problem, we have crossed the TGR(hAOGEN) with a TGR harboring the hREN gene. This TGR(hREN)IOJ was developed m Japan In- Correspondence to Frredrrch C Luft, Franz Volhard Clnuc, Wrltberg Strasse 50, 13122 Berlin, FRG E-marl fcluft@ orton rz mdc-berlm de 0 1997 Amerrcan Heart Assocratron, Inc formation on this rat has not yet been published Offspring from this cross harbor both transgenes and therefore have all the necessary components of the hu...