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Researchers
  • Prof.  Joseph Yanai
Prof Joseph Yanai
 
Biography
 
1972 - Ph.D. Univ. of Colorado. 
1978 - Present, Lecturer, Senior Lecturer; Associate Professor; Professor.
1991 - Present, Professor (Adjunct); Department of Pharmacology, Duke University Medical School, Durham, North Carolina, USA, Email: ​jyanai@duke.edu.
 
 
Research Interests
 
Ascertaining in the mouse and chick models the mechanisms of neural and behavioral birth defects induced by various agents, mainly organophosphates and heroin, and their reversal with mesenchymal and neural stem cell (MSC, NSC) therapies; understanding the mechanisms by which the transplanted cells exert their therapeutic action.
 
In the mouse model, the study of the mechanisms focuses on behaviors related to the septohippocampal cholinergic innervation (Morris and eight-arm mazes). Our hypothesis is that abolishment in the hippocampus of cholinergic receptor-induced translocation/activation of PKCγ represents a principal component in the mechanism by which various substances induces neurobehavioral birth defects.
 
Our parallel chick model, which controls for maternal confounds, involves perturbation by the teratogen of imprinting related to defects where the mechanism is again abolishment of translocation/activation of PKCγ in the IMHV (IMM) nucleus.
In both models we are promoting the novel hypothesis that one major mechanism by which stem cells exert their therapeutic action is by inducing neurogenesis, i.e. proliferation of endogenous precursors.
 
In both models the changes in synaptic function may be regulated by the teratogen- induced epigenetic alterations.

Research milestones old and new (text citations listed at the bottom of the website):
 
Being one of the founders of the modern Behavioral Teratology, thus expanded the concept by introducing the study of the mechanisms of the defects termed “Neurobehavioral Teratology” (Yanai 1984, Yaniv et al 2004).
 
Developing the model for the reversal of neurobehavioral teratogenicity, in mice, by way of neural grafting (Steingart et al 2000, Yanai & Pick 1988).
 
Reversal of neurobehavioral teratogenicity in mice by manipulations of the A10 regulating neural pathways (Yanai et al 1987, Yanai et al 1989).
Reversal of neurobehavioral teratogenicity, in mice, via nicotine therapy (Beer et al 2005).
 
Reversal of neurobehavioral teratogenicity, in mice, via transplantation of various types of stem cells (Ben-Shaanan et al 2008, Izrael et al 2004, Katz et al 2008, Turgeman et al 2011, Yanai et al 2005, Yanai et al 1995a).
 
The establishment of models for the reversal of neurobehavioral deficits in the avian: a. Parkinson’s disease in the adult chicken (Yanai et al 1995b), b. reversal of neurobehavioral teratogenicity in a chick embryo model (Pinkas et al 2013).
 
Establishing the principle that one major mechanism by which stem cells exert their therapeutic effect is the induction of neurogenesis (Ben-Shaanan et al 2008, Pinkas et al 2013).
 
Recent Findings
 
Pregnant female mice were exposed to heroin, organophosphate or other substances. Their offspring showed, upon maturity, an abolishment of cholinergic receptor-induced activation/translocation of PKCγ in the septohippocampal cholinergic innervation, paralleled with defects in the hippocampus-related Morris and eight-arm maze behaviors.
 
Understanding the synaptic mechanism of the behavioral defects enabled reversal of the neurobehavioral teratogenicity using the various therapies described above:
 
Further studies suggest that one major mechanism by which the transplanted cells exerted their therapeutic action is by the induction of neurogenesis and synaptogenesis in the teratogen-impaired brain. Further studies demonstrated impairment of neurogenesis (doublecortin and neurogenesis-related genes) after prenatal exposure to teratogen (chlorpyrifos). Transplantation of MSC restored normal neurogenesis. 
 
In the chick model, incubated eggs were injected with various teratogens. The hatched chicks showed marked defects in their imprinting behavior, which was correlated with abolishment of cholinergic-induced activation/translocation of PKCγ in their IMHV (IMM) nucleus. Additionally, neurogenesis was impaired as attested to by reduced doublecortin labeling and neurogenesis-related genes. Stem cells transplanted to the chick embryo via the blood vessels attached to the chorio-allantoic membrane reach the embryonic brain and restored normal neurogenesis. 
 
Currently, we are testing the hypothesis, in both models, that the changes described may be regulated by the teratogen-induced epigenetic alterations. 
 
The study of the reversal of heroin and chlorpyrifos (an organophosphate)-induced neurobehavioral teratogenicity serves as examples: NSC derived from normal developing brains (Fig. 1) were grafted into the hippocampus of mice offspring who were exposed prenatally to the teratogens and showed hippocampus related defects in behavior and PKC activation/translocation.
 
Fig. 1 Differentiation of ES-NSC dissociated precursor cells into neural lineage cells.
A. ES-NSC grown in the presence of the growth factors EGF and bFGF are positive for neural marker- Nestin. B-D. Growth factor removal promoted the differentiation of ES-NSC into neurons, oligodendrocyte and astrocytes; B. NF160 positive differentiated neurons, B’. High proportion of NF positive cells exhibit cholinergic marker ChAT. C. O4 positive oligodendrocytes. D. GFAP positive astrocytes. E. PCR Expression of Neural genes with and without growth factor. Each band of the neural lineage genes tested was normalized in relation to the house keeping gene GAPDH. Size bars: A-D: 100 μm. F. Quantitative representation of the gene expression findings with and without (w/o) growth factors (GF).
 
Figure 1 Differentiation of ES-NSC dissociated precursor cells into neural lineage cells.
  
The transplanted cells survived and differentiated in the host hippocampus as shown in Fig. 2. Offspring exposed prenatally to heroin had at maturity deficits in Morris maze behavior (A) and in the mechanistically-related absolute abolishment of cholinergic receptor-induced activation/translocation of hippocampal PKCγ (B). Transplantation of NSC into the impaired hippocampus reversed the neurobehavioral defects (Fig. 3). 
 
Fig. 2
Grafted BrdU-labeled NSC identified in the brain CM-DiI-Labeled adult (subventricular zone-derived) NSC post transplantation were shown to differentiate to cholinergic neurons
A. Grafted BrdU-labeled NSC identified in the brain of the teratogen-impaired brain by immunofluorescent staining (green). Some of the transplanted cells acquire markers of specific neural lineages. In the present case double labeling BrdU+, GFAP+ astrocytes (red, confocal microscopy).
B. CM-DiI-Labeled adult (subventricular zone-derived) NSC post transplantation were shown to differentiate to cholinergic neurons expressing ChAT (arrows, DiI - red, DAPI – blue).
 
 
Fig 3.
Transplantation of NSC reversed the prenatal heroin-induced deficits in Morris maze behavior Transplantation of NSC reversed the heroin-induced desensitization of hippocampal PKCg.
A. Transplantation of NSC reversed the prenatal heroin-induced deficits in Morris maze behavior. Numbers represent the time spent to reach the platform (mean±SEM).
Control (pooled) = Prenatal control – postnatal medium or NSC.
H-C = Prenatal heroin - postnatal medium.
H-NP = Prenatal heroin - postnatal NSC.
P<0.001.
B. Transplantation of NSC reversed the heroin-induced desensitization of hippocampal PKCg.
C-C = Prenatal control – postnatal medium
C-NP = Prenatal control - postnatal NSC
H-C = Prenatal heroin - postnatal medium.
H-NP = Prenatal heroin - postnatal NSC
P<0.05.
 
We hypothesize that one major mechanism by which the stem cells exert their therapeutic action is the induction of neurogenesis in the host brain. Indeed, transplantation of NSC induced increased production of endogenous cells in the brain (Fig. 4.)
 
Fig.4
Neurogenesis in the dentate gyrus in transplanted versus control heroin-exposed mice
Neurogenesis in the dentate gyrus in transplanted versus control heroin-exposed mice. Few BrdU-labeled cells were observed (light stain, Alexa 488) in the granular cell layer of mice exposed prenatally to heroin and sham operated (A), but significantly more in mice transplanted with NSC (B).
 
Chick model:
Chicks were exposed to various teratogens prehatch (in the incubating egg). After hatching, they showed alterations in PKCγ in the IMHV nucleus (Fig. 5A) and concomitant deficits in the IMHV-related imprinting behavior (Fig. 5B).
 
Fig. 5
A. Preference ratio in control chicks and chicks with prehatch exposure to nicotine, chlorpyrifos or heroin (means ±SEM). ***P<0.001, * P<0.05) versus respective controls (ANOVA). P<0.001 for the difference from no preference (score = 0.5). Preference ratio in control chicks and chicks with prehatch exposure to nicotine, chlorpyrifos or heroin (means ±SEM).
B. Effect of prehatch exposure to chlorpyrifos basal membrane levels of PKC isoforms. Data represent means and standard errors of the differences from control levels (means ±SEM). * P<0.05, **P<0.01 versus zero change. Effect of prehatch exposure to chlorpyrifos basal membrane levels of PKC isoforms
  
Subsequently we have established a model for transplantation of stem cells into the brain of the chick embryo (Fig. 6). Prehatch- exposure to chlorpyrifos impaired neurogenesis as demonstrated with doublecortin labeling. Transplantation of MSC to the chick embryo restored normal neurogenesis (Fig. 7). 
Fig 6. IV transplanted stem cells in the chick embryo migrated to its brain and survived. CM-Dil labeled cells were IV transplanted into E13 chick embryos and the cells were tracked in posthatch 1 chick embryos' brains. Transplanted cells have migrated along the blood vessels and reached the third ventricle of the chick embryos' brains. Fig 6. IV transplanted stem cells in the chick embryo migrated to its brain and survived
Fig. 7. Reversal of neuroteratogenicity in a chick-chlorpyrifos (CPF) model: Transplantation of MSC reversed prehatch chlorpyrifos-induced alterations in neurogenesis (doublecortin labeling)
The X axis (0.0) represents the transplanted (media) group (N=7). Where the bars represent proportional differences from Control Sham C TR, control transplanted (with MSC); CPF SH, CPF sham; CPF TR, CPF transplanted. N = number of brains.
Fig. 7. Reversal of neuroteratogenicity in a chick-chlorpyrifos (CPF) model
Recent studies identified neurogenesis-related genes that were down-regulated by the prehatch exposure to chlorpyrifos as is shown in Fig. 8. Transplantation of MSC to the chick embryo restored normal expression of these genes. 
 
Fig. 8
Fig. 8. The effects of MSC transplantation on neurogenesis-related gene expression in the lateral striatum area
Fig. 8. The effects of MSC transplantation on neurogenesis-related gene expression in the lateral striatum area following prenatal exposure to CPF.
Left / Right – sides of brain; numbers at the bottom of each column = N. TR - transplanted
* P<0.05; ** P<0.01; *** P<0.001.
 
 
 
Research Projects
 
Mouse and Chick Models:
a.
 
 
 
Neurobehavioral teratogenicity: assessing behavioral birth defects induced by various teratogens and ascertaining their mechanisms - a behavioral/molecular/epigenetic study: investigating teratogen-induced defects in neurogenesis as a primary cause of cholinergic receptor regulation of activation/translocation of PKC isoforms, possible epigenetic regulation and the apparent involvement of these processes in the mechanism of neurobehavioral birth defects.
b.
 
Stem cell therapy for neurobehavioral teratogenicity: applying stem cell transplantation both as a clinical therapy for reversal of the defects and as a probe for understanding the mechanisms of the defects.
  ​​
Selected Publications
Yanai, J., Z. Greenfeld, U. Laxer, C.G. Pick, D. Trombka and D. Weinstein. CNS changes after early barbiturate exposure: mechanisms and reversal. In. T. Fujii and P.M. Adams. (eds). Functional Teratogenesis, pp. 121-130, Tokyo-University Press (1987).
 
Yanai, J., and C.G. Pick. Neuron transplantation reverses phenobarbital-induced behavioral birth defects in mice. Int. J. Dev. Neurosci., 6:409-416 (1988).
 
Yanai, J., U. Laxer, C. G. Pick and D. Trombka. Dopaminergic denervation reverses behavioral deficits induced by prenatal exposure to phenobarbital. Dev. Brain Research, 48:255-261 (1989).
 
Yanai, J., T. Doetchman, N. Laufer, J. Maslaton, S. Mor-Yosef, M. Shani and D. Sofer. Embryonic cultures but not zygotes transplanted to the mouse's brain grow rapidly without immunosuppression. Int. Journal of Neuroscience 81:21-26 (1995).

Yanai, J., T. Doetchman, N. Laufer, J. Maslaton, S. Mor-Yosef, M. Shani and D. Sofer. Embryonic cultures but not embryos transplanted to the mouse's brain grow rapidly without immunosuppression. Int. Journal of Neuroscience 81:21-26 (1995).
 
Yanai, J., W. Silverman and D. Shamir. An avian model for the reversal of 6-hydroxydopamine induced rotating behavior by neural grafting. Neuroscience Letters 187:153-156 (1995).
 
Steingart, R. A., W. F. Silverman, S. Barron, T. A. Slotkin, Y. Awad and J. Yanai. Neural grafting reverses prenatal drug-induced alterations in hippocampal PKC and related behavioral deficits. Dev. Brain. Research, 125:9-19 (2000).
 
Yaniv, S. P., Z. Naor and J. Yanai. Prenatal heroin exposure alters cholinergic receptor stimulated translocation and basal levels of the PKCbII and PKCg isoforms. Brain Research Bulletin, 63: 339–349 (2004).

Izrael, M., E. A. Van der Zee, T. A. Slotkin and J. Yanai. Cholinergic Synaptic Signaling Mechanisms Underlying Behavioral Teratogenicity: Effects of Nicotine, Chlorpyrifos and Heroin Converge on PKC Translocation in the IMHV and on Imprinting Behavior in an Avian Model J. Neuroscience Research, 78:499–507 (2004).
 
Beer, A., T. A. Slotkin, F. J. Seidler and J. Yanai. Nicotine therapy in adulthood reverses the synaptic and behavioral deficits elicited by prenatal exposure to phenobarbital. Neuropsychopharmacology, 30: 156–165 (2005).
 
Wormser, U., M. Izrael, E.A. Van der Zee and J. Yanai. A chick model for the mechanisms of mustard gas neurobehavioral teratogenicity. Neurotoxicology and Teratology, 27:65–71(2005).
 
Yanai, J, T. Ben-Hur, T.A. Slotkin and S. Katz. Neural progenitors for the reversal of heroin neurobehavioral teratogenicity. Paper presented at the 3rd Annual Meeting of the International Society for Stem Cell Research, 2005. Abstract published in the Proceedings, p259.

Katz S., T. Ben-Hur , T. L. Ben-Shaanan, and J. Yanai. Reversal of heroin neurobehavioral teratogenicity by grafting of neural progenitors. Journal of Neurochemistry, 104:38-49 (2008).

Ben-Shaanan T. L., T. Ben-Hur, and J. Yanai. Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain. Molecular Psychiatry, 13: 222-231 (2008).

Billauer-Haimovitch, H., S. Dotan, R. Langford, A. Pinkas, T.A. Slotkin and J. Yanai. Reversal of chlorpyrifos neurobehavioral teratogenicity in mice with nicotine and neural progenitors therapies. Behavioural Brain Research, 205(2): 499-504 (2009).

Kazma, M., M. Izrael, M. Revel, J. Chebath and J. Yanai. Survival, differentiation and reversal of heroin neurobehavioral teratogenicity in mice by transplanted neural stem cells derived from embryonic stem cells. Journal of Neuroscience Research 88(2): 315-323 (2009).

Yanai, J., A. Pinkas, F. Seidler, I. Ryde, E. Van der Zee and T. Slotkin. Neurobehavioral teratogenicity of sarin in an avian model. Neurotoxicology and Teratology, 31(6): 406-412 (2009).

Dotan, S., A. Pinkas, T. A. Slotkin and J. Yanai. An avian model for neural stem cell transplantation. Neurotoxicology and Teratology, 32: 182–186 (2010).
 
Turgeman, G., A. Pinkas, T. Slotkin, M. Tfillin, R. Langford and J. Yanai. Reversal of chlorpyrifos neurobehavioral teratogenicity in mice by allographic transplantation of adult subventricular zone-derived neural stem cells. Journal of Neuroscience Research 89: 1185-1193 (2011).
 
Abdul-Ghani, S., J. Yanai, R. Abdul-Ghani, J. Yanai, A. Pinkas and Z. Abdeen. The teratogenicity and behavioral teratogenicity of di(2-ethylhexyl) phthalates (DEHP) and di-butyl Phthalates (DBP) in a chick model. Neurotoxicology and Teratology, 34: 56–62 (2012)

Hamisha, K. N., M. Tfilin, J. Yanai and G. Turgeman. Mesenchymal stem cells can prevent alterations in behavior and neurogenesis induced by Aß25-35 administration. J. Mol. Neurosci. 55: 1006-1013 (2015)
 
Pinkas A., G. Turgeman, S. Tayeb and J. Yanai. An avian model for ascertaining the mechanisms of organophosphate neuroteratogenicity and its therapy with mesenchymal stem cell transplantation. Neurotoxicology and teratology, Neurotoxicology and teratology 50: 73-81 (2015)
 
Books
Yanai, J. (Ed) Neurobehavioral Teratology. Elsevier, Amsterdam. (1984).

Yanai, J., R. Bauml, P. Eldar and J.M. Rosenfeld (Eds) Alcohol Dependence the Family and the Community. Freund, London. (1988).
 
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