- Email: [email protected]
SSRIs and placental dysfunction
Correspondence/Medical Hypotheses 77 (2011) 308–313
point (weighted-labeled dashed-line). Indeed, it seems reasonable to consider a higher relative weight for a data point issued from, say, a 1332-sample study such as Willott [2] than from a 25-sample one [3]. While the same caution must be exercised in interpreting the linear regression, a clear negative trend can be observed. This claim is further supported by the fact that, what is plotted here is the maximum of the data set provided by each study, and not just some average. With a larger sample set, and without a general trend, the reported maximum would increase as one has more chance to observe a long survival case. However, what is observed is the opposite, strongly indicating a negative trend in the spermatozoa survival time in the vagina. How to explain this reduction of average (and maximum) vaginal spermatozoa observation in the context of sexually assaulted female victims? Does it corresponds to a reduction of spermatozoa concentration in ejaculate? To a reduction of spermatozoa vitality? To physicochemical modifications of the site of sampling (vagina) decreasing faculties of conservation of the spermatozoa? A conclusion is that it seems reasonable to see there physiological consequences of environmental effects described as limiting spermatozoa viability [4]. Mix phenomenon may also be possible. Further studies will have to determine if such a comparable tendency exists on other anatomical sites (internal and external anal, mouth) with similar environmental side-effects. Anyway, this reduction in survival (thus of observation) of spermatozoa involves a risk of false-negative result for forensic detection of semen for rape purpose. In such first-line negative cases, perhaps this examination could be followed by other methods of detection (secondline examination) such as a search for prostate-specific-antigen (PSA) or seminal acid phosphatase test (biochemical method) and/or for foreign male DNA (genetic method) [5]. References [1] Davies A, Wilson E. The persistence of seminal constituents in the human vagina. Forensic Sci 1974;3:45–55. [2] Skakkebaek NE, Jorgensen N, Main KM, et al. Is human fecundity declining? Int J Androl 2006;29:2–11. [3] Willott GM, Allard JE. Spermatozoa - their persistence after sexual intercourse. Forensic Sci Int 1982;19:135–54. [4] Stein IF, Cohen MR. Sperm survival at estimated ovulation time: prognostic significance. Fertil Steril 1950;1:169–75. [5] Sibille I, Duverneuil C, Lorin de la Grandmaison G, et al. Y-STR DNA amplification as biological evidence in sexually assaulted female victims with no cytological detection of spermatozoa. Forensic Sci Int 2002;125:212–6.
P. Charlier Department of Forensic Medicine and Pathology, University Hospital R. Poincar (AP-HP, UVSQ), 104 R. Poincar boulevard, 92380 Garches, France HALMA-IPEL, UMR 8164 CNRS, Lille 3 University, Villeneuve d’Ascq, France Department of Medical Ethic, Paris 5 University, Paris, France Tel.: +33 1 47 10 76 80/89; fax: +33 1 47 10 76 83. E-mail address: [email protected] L. Mathelin LIMSI, CNRS, Orsay, France A.Benredjem Department of Forensic Medicine and Pathology, University Hospital R. Poincar (AP-HP, UVSQ), Garches, France G. Lorin de la Grandmaison Department of Forensic Medicine and Pathology, University Hospital R. Poincar (AP-HP, UVSQ), Garches, France doi:10.1016/j.mehy.2011.05.024
311
SSRIs and placental dysfunction
Major Depressive Disorder (MDD) can be a serious medical concern for 10–16% of pregnant women [1]. MDD in pregnancy often necessitates treatment, generally with a selective serotonin reuptake inhibitor (SSRI) antidepressant. However, the overall safety profile of use of SSRIs in pregnancy remains unclear. Several studies suggest a teratogenic potential of the SSRI class, consistent with preclinical evidence [2]. These reported teratogenic effects are generally cardiovascular, often described as septal defects [2]. Persistent Pulmonary Hypertension of the Newborn (PPHN), a neonatal condition associated with significant morbidity and mortality, has also been reported with SSRI [3]. However, current evidence of SSRI teratogenicity stems from studies affected by several methodological weaknesses (i.e., lack of investigations using control groups of untreated depressed mothers, confounding by indication, and recall bias) [2]. Among all the SSRIs, there is more evidence to support an association between birth defects and first-trimester exposure to paroxetine [1,2]. Epidemiological studies have shown that infants born to women who experienced first trimester paroxetine exposure had elevated risk of cardiovascular malformations compared to registry controls [4]. In a recent metaanalysis paroxetine was seen to be associated with a 1.7-fold increased risk of cardiac malformations [5]. It has been suggested that the higher frequency of teratogenic effects reported for paroxetine might depend on specific pharmacologic features of this drug compared with other SSRIs, although it is difficult to test this hypothesis [1,2]. We hypothesize that by interfering with certain placental enzymes in the Tryptophan (TRP) metabolic pathway, SSRIs including paroxetine may cause adverse effects in the following ways: (1) Tryptophan (TRP) is an important amino acid in several metabolic pathways both within the placenta as well as outside the placenta. TRP is either metabolized to serotonin or niacin via different pathways. TRP pyrrolase is a liver enzyme that metabolizes TRP to kyneurenine (KYN), an intermediate pathway product of TRP metabolism to niacin. Several antidepressants including SSRIs have been shown to inhibit this enzyme in the liver [6–8]. In the placenta TRP is metabolized to KYN via a rate limiting immunomodulatory enzyme indolamine 2,3 dioxygenase (IDO) [9]. While the direct effects of SSRIs on TRP metabolism in placenta have not been studied, we hypothesize that just like they inhibit TRP Pyrrolase and in turn inhibit TRP metabolism to KYN in liver, they possibly inhibit the TRP metabolism to KYN in placenta by inhibiting IDO. We hypothesize that it is by the inhibition of this important immunomodulatory enzyme IDO in placenta, SSRIs may cause adverse effects in pregnancy. (2) IDO is strongly expressed in the cells of first trimester deciduas [9]. In the first two trimesters, IDO activity is mainly localized to placental syncytiotrophoblast, stroma and macrophages. TRP is an essential amino acid required for the activity of T lymphocytes in placenta. IDO thus serves an important immunomodulatory role by causing TRP depletion, hence leading to decreased activity of T lymphocytes and thus preventing a possible placental rejection. Inhibition of IDO could lead to accumulation of TRP which could cause the T lymphocyte activation and increased risk for placental rejection [10]. Placental rejection from over activity of T cells may result in spontaneous habitual abortions or several phenomenon seen in autoimmune diseases and IDO play an important role in suppressing it [11]. IDO activity may also play a protective function against infection in pregnancy as TRP is an essential amino acid required for bacterial proliferation.
312
Correspondence/Medical Hypotheses 77 (2011) 308–313
Tryptophan Inhibits IDO/ TRP pyrrolase
SSRIs including Paroxetine (Liver/ Decidua and Syncytiotrophoblast)
Serotonin
[12] Charnock-Jones DS, Burton GJ. Placental vascular morphogenesis. Baillieres Best Pract Res Clin Obstet Gynaecol 2000;14:953–68. [13] Sedlmayr P, Blaschitz A, Wintersteiger R, Semlitsch M, Hammer A, MacKenzie CR, et al. Localization of indoleamine 2,3-dioxygenase in human female reproductive organs and the placenta. Mol Hum Reprod 2002;8(4):385–91.
Kynurenine KYN-OHase
Quinolinic Acid (3) Later in pregnancy, there is a shift of expression of IDO to fetal endothelial cells in terminal villi suggesting a change in the function of these enzymes from immunosuppression at the maternal–fetal interface in early pregnancy, to later regulation of feto-placental blood flow or placental metabolism by regulating the amount of TRP available for the production of serotonin, which acts as a powerful vasoconstrictor agent in the placenta. It is possible that fetal endothelial IDO may prevent free radical damage to the endothelium, and prevent or minimize vasoconstriction, thereby maintaining the vasodilatation which is thought to be essential for adequate fetal oxygenation [12]. (4) IDO activity is also found in tissues other than placenta as well, such as lungs and small intestine [13]. As explained above, inhibition of IDO can cause a shift of the TRP pathway towards serotonin production instead of KYN. Serotonin is a known vasoconstrictor and excessive production of serotonin may cause pulmonary vasoconstriction resulting in persistent pulmonary hypertension of the newborn (PPHN). (5) Placenta is also a rich source of polyunsaturated fatty acid and is an abundant source of lipid peroxidation and thus free radical formation including ROS (reactive oxygen species) and RNS (reactive nitrogen species). The IDO uses the ROS as a cofactor. If the IDO is inhibited by SSRIs it can lead to the accumulation of ROS which may cause oxidative stress and free radical damage. It is possible that the congenital cardiac malformation seen with SSRIs use could be secondary to free radical damage [10]. References [1] Soufia M etal. SSRIs and pregnancy: a review of the literature Encephale 2010 Dec;36(6):513–6. Epub 2010 Apr 3. [2] Tuccori M et al. Use of selective serotonin reuptake inhibitors during pregnancy, risk of major, cardiovascular malformations: an update. Postgrad Med 2010;122(4):49–65. [3] Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. New Eng J Med 2006;354(6):579–87. [4] Klln BA, Otterblad Olausson P. Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infant congenital malformations. Birth Defects Res A Clin Mol Teratol 2007;79(4):301–8. [5] Bar-Oz B, Einarson T, Einarson A, et al. Paroxetine and congenital malformations: meta-analysis and consideration of potential confounding factors. Clin Ther 2007;29(5):918–26. [6] Bano S et al. Acute effects of serotonergic antidepressants on tryptophan metabolism and corticosterone levels in rats. Pak J Pharm Sci 2010;23(3):266–72. [7] Badawy AA, Morgan CJ. Effects of acute paroxetine administration on tryptophan metabolism and disposition in the rat. Br J Pharmacol 1991;102(2):429–33. [8] Badawy AA-B. The acute effects of lofepramine and desmethylimpramine on tryptophan metabolism and disposition in the rat. Br J Pharmacol 1986;89:859P. [9] Bonney EA, Matzinger P. Much IDO about Pregnancy. Nat Med 1998;4: 1128–9. [10] Ligam P, Manuelpillai U, Wallace EM, Walker D. Localisation of indoleamine 2,3-dioxygenase and kynurenine hydroxylase in the human placenta and decidua: implications for role of the kynurenine pathway in pregnancy. Placenta 2005;26(6):498–504. [11] Munn DH. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 1998;281(5380):1191–3.
Alok Banga Division of Child and Adolescent Psychiatry, Department of Psychiatry, University of Connecticut School of Medicine and Health Care, Farmington, CT, USA Venkatesh Handratta1 Division of Child and Adolescent Psychiatry, Department of Psychiatry, University of Connecticut School of Medicine and Health Care, 263 Farmington Avenue, Farmington, CT 06030, USA Tel.: +1 8606792730; fax: +1 8606701296 Lobna Ibrahim NIMH, USA Daniel F. Connor Division of Child and Adolescent Psychiatry, Department of Psychiatry, University of Connecticut School of Medicine and Health Care, Farmington, CT, USA doi:10.1016/j.mehy.2011.05.023 1
He is currently in community practice in Maryland, USA.
Reprogramming neurons by microRNAs into iPSCs to treat Parkinson’s disease
Sir, Parkinson’s disease (PD) is the second most common neurodegenerative disease. Cell replacement therapy has been tested clinically in PD. But, only embryonic stem cells (ESCs) can migrate to the damaged regions of brain tissue, engraft, and differentiate [1]. Due to ethical debate about ESCs, researchers developed a technique that reprograms cells into induced pluripotent stem cells (iPSCs) through viral expression of four transcription factors [2]. However, one important limiting factor for clinical application of iPSCs is the presence of viral vectors [3]. Recently, it has demonstrated that miRNAs do function in the reprogramming cells [4]. Nevertheless, transplantation of exogenous iPSCs carries some limitations, e.g., the immunocompatibility issues, survival, and progression of disease in the transplanted tissue [5]. Here, we hypothesized that an efficient microRNAs-based delivery system could induce iPSCs into the striatum and/or substantia nigra. For endogenous replacement, it should be noted that teratoma formation is an inherent feature of iPSCs. As this tumorigenic activity is lost following differentiation, pharmacological approaches, and genetic manipulation can be adopted to promote the neural differentiation. Finally, careful physiological evaluations are required to confirm the same function of new dopaminergic neurons. Hopefully, these invivo patient-specific iPSCs can bring a new avenue for cell replacement therapies. References [1] Srivastava AS, Shenouda S, Mishra R, Carrier E. Transplanted embryonic stem cells successfully survive, proliferate, and migrate to damaged regions of the mouse brain. Stem Cells 2006;24:1689–94. [2] Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006;126:663–76.
point (weighted-labeled dashed-line). Indeed, it seems reasonable to consider a higher relative weight for a data point issued from, say, a 1332-sample study such as Willott [2] than from a 25-sample one [3]. While the same caution must be exercised in interpreting the linear regression, a clear negative trend can be observed. This claim is further supported by the fact that, what is plotted here is the maximum of the data set provided by each study, and not just some average. With a larger sample set, and without a general trend, the reported maximum would increase as one has more chance to observe a long survival case. However, what is observed is the opposite, strongly indicating a negative trend in the spermatozoa survival time in the vagina. How to explain this reduction of average (and maximum) vaginal spermatozoa observation in the context of sexually assaulted female victims? Does it corresponds to a reduction of spermatozoa concentration in ejaculate? To a reduction of spermatozoa vitality? To physicochemical modifications of the site of sampling (vagina) decreasing faculties of conservation of the spermatozoa? A conclusion is that it seems reasonable to see there physiological consequences of environmental effects described as limiting spermatozoa viability [4]. Mix phenomenon may also be possible. Further studies will have to determine if such a comparable tendency exists on other anatomical sites (internal and external anal, mouth) with similar environmental side-effects. Anyway, this reduction in survival (thus of observation) of spermatozoa involves a risk of false-negative result for forensic detection of semen for rape purpose. In such first-line negative cases, perhaps this examination could be followed by other methods of detection (secondline examination) such as a search for prostate-specific-antigen (PSA) or seminal acid phosphatase test (biochemical method) and/or for foreign male DNA (genetic method) [5]. References [1] Davies A, Wilson E. The persistence of seminal constituents in the human vagina. Forensic Sci 1974;3:45–55. [2] Skakkebaek NE, Jorgensen N, Main KM, et al. Is human fecundity declining? Int J Androl 2006;29:2–11. [3] Willott GM, Allard JE. Spermatozoa - their persistence after sexual intercourse. Forensic Sci Int 1982;19:135–54. [4] Stein IF, Cohen MR. Sperm survival at estimated ovulation time: prognostic significance. Fertil Steril 1950;1:169–75. [5] Sibille I, Duverneuil C, Lorin de la Grandmaison G, et al. Y-STR DNA amplification as biological evidence in sexually assaulted female victims with no cytological detection of spermatozoa. Forensic Sci Int 2002;125:212–6.
P. Charlier Department of Forensic Medicine and Pathology, University Hospital R. Poincar (AP-HP, UVSQ), 104 R. Poincar boulevard, 92380 Garches, France HALMA-IPEL, UMR 8164 CNRS, Lille 3 University, Villeneuve d’Ascq, France Department of Medical Ethic, Paris 5 University, Paris, France Tel.: +33 1 47 10 76 80/89; fax: +33 1 47 10 76 83. E-mail address: [email protected] L. Mathelin LIMSI, CNRS, Orsay, France A.Benredjem Department of Forensic Medicine and Pathology, University Hospital R. Poincar (AP-HP, UVSQ), Garches, France G. Lorin de la Grandmaison Department of Forensic Medicine and Pathology, University Hospital R. Poincar (AP-HP, UVSQ), Garches, France doi:10.1016/j.mehy.2011.05.024
311
SSRIs and placental dysfunction
Major Depressive Disorder (MDD) can be a serious medical concern for 10–16% of pregnant women [1]. MDD in pregnancy often necessitates treatment, generally with a selective serotonin reuptake inhibitor (SSRI) antidepressant. However, the overall safety profile of use of SSRIs in pregnancy remains unclear. Several studies suggest a teratogenic potential of the SSRI class, consistent with preclinical evidence [2]. These reported teratogenic effects are generally cardiovascular, often described as septal defects [2]. Persistent Pulmonary Hypertension of the Newborn (PPHN), a neonatal condition associated with significant morbidity and mortality, has also been reported with SSRI [3]. However, current evidence of SSRI teratogenicity stems from studies affected by several methodological weaknesses (i.e., lack of investigations using control groups of untreated depressed mothers, confounding by indication, and recall bias) [2]. Among all the SSRIs, there is more evidence to support an association between birth defects and first-trimester exposure to paroxetine [1,2]. Epidemiological studies have shown that infants born to women who experienced first trimester paroxetine exposure had elevated risk of cardiovascular malformations compared to registry controls [4]. In a recent metaanalysis paroxetine was seen to be associated with a 1.7-fold increased risk of cardiac malformations [5]. It has been suggested that the higher frequency of teratogenic effects reported for paroxetine might depend on specific pharmacologic features of this drug compared with other SSRIs, although it is difficult to test this hypothesis [1,2]. We hypothesize that by interfering with certain placental enzymes in the Tryptophan (TRP) metabolic pathway, SSRIs including paroxetine may cause adverse effects in the following ways: (1) Tryptophan (TRP) is an important amino acid in several metabolic pathways both within the placenta as well as outside the placenta. TRP is either metabolized to serotonin or niacin via different pathways. TRP pyrrolase is a liver enzyme that metabolizes TRP to kyneurenine (KYN), an intermediate pathway product of TRP metabolism to niacin. Several antidepressants including SSRIs have been shown to inhibit this enzyme in the liver [6–8]. In the placenta TRP is metabolized to KYN via a rate limiting immunomodulatory enzyme indolamine 2,3 dioxygenase (IDO) [9]. While the direct effects of SSRIs on TRP metabolism in placenta have not been studied, we hypothesize that just like they inhibit TRP Pyrrolase and in turn inhibit TRP metabolism to KYN in liver, they possibly inhibit the TRP metabolism to KYN in placenta by inhibiting IDO. We hypothesize that it is by the inhibition of this important immunomodulatory enzyme IDO in placenta, SSRIs may cause adverse effects in pregnancy. (2) IDO is strongly expressed in the cells of first trimester deciduas [9]. In the first two trimesters, IDO activity is mainly localized to placental syncytiotrophoblast, stroma and macrophages. TRP is an essential amino acid required for the activity of T lymphocytes in placenta. IDO thus serves an important immunomodulatory role by causing TRP depletion, hence leading to decreased activity of T lymphocytes and thus preventing a possible placental rejection. Inhibition of IDO could lead to accumulation of TRP which could cause the T lymphocyte activation and increased risk for placental rejection [10]. Placental rejection from over activity of T cells may result in spontaneous habitual abortions or several phenomenon seen in autoimmune diseases and IDO play an important role in suppressing it [11]. IDO activity may also play a protective function against infection in pregnancy as TRP is an essential amino acid required for bacterial proliferation.
312
Correspondence/Medical Hypotheses 77 (2011) 308–313
Tryptophan Inhibits IDO/ TRP pyrrolase
SSRIs including Paroxetine (Liver/ Decidua and Syncytiotrophoblast)
Serotonin
[12] Charnock-Jones DS, Burton GJ. Placental vascular morphogenesis. Baillieres Best Pract Res Clin Obstet Gynaecol 2000;14:953–68. [13] Sedlmayr P, Blaschitz A, Wintersteiger R, Semlitsch M, Hammer A, MacKenzie CR, et al. Localization of indoleamine 2,3-dioxygenase in human female reproductive organs and the placenta. Mol Hum Reprod 2002;8(4):385–91.
Kynurenine KYN-OHase
Quinolinic Acid (3) Later in pregnancy, there is a shift of expression of IDO to fetal endothelial cells in terminal villi suggesting a change in the function of these enzymes from immunosuppression at the maternal–fetal interface in early pregnancy, to later regulation of feto-placental blood flow or placental metabolism by regulating the amount of TRP available for the production of serotonin, which acts as a powerful vasoconstrictor agent in the placenta. It is possible that fetal endothelial IDO may prevent free radical damage to the endothelium, and prevent or minimize vasoconstriction, thereby maintaining the vasodilatation which is thought to be essential for adequate fetal oxygenation [12]. (4) IDO activity is also found in tissues other than placenta as well, such as lungs and small intestine [13]. As explained above, inhibition of IDO can cause a shift of the TRP pathway towards serotonin production instead of KYN. Serotonin is a known vasoconstrictor and excessive production of serotonin may cause pulmonary vasoconstriction resulting in persistent pulmonary hypertension of the newborn (PPHN). (5) Placenta is also a rich source of polyunsaturated fatty acid and is an abundant source of lipid peroxidation and thus free radical formation including ROS (reactive oxygen species) and RNS (reactive nitrogen species). The IDO uses the ROS as a cofactor. If the IDO is inhibited by SSRIs it can lead to the accumulation of ROS which may cause oxidative stress and free radical damage. It is possible that the congenital cardiac malformation seen with SSRIs use could be secondary to free radical damage [10]. References [1] Soufia M etal. SSRIs and pregnancy: a review of the literature Encephale 2010 Dec;36(6):513–6. Epub 2010 Apr 3. [2] Tuccori M et al. Use of selective serotonin reuptake inhibitors during pregnancy, risk of major, cardiovascular malformations: an update. Postgrad Med 2010;122(4):49–65. [3] Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. New Eng J Med 2006;354(6):579–87. [4] Klln BA, Otterblad Olausson P. Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infant congenital malformations. Birth Defects Res A Clin Mol Teratol 2007;79(4):301–8. [5] Bar-Oz B, Einarson T, Einarson A, et al. Paroxetine and congenital malformations: meta-analysis and consideration of potential confounding factors. Clin Ther 2007;29(5):918–26. [6] Bano S et al. Acute effects of serotonergic antidepressants on tryptophan metabolism and corticosterone levels in rats. Pak J Pharm Sci 2010;23(3):266–72. [7] Badawy AA, Morgan CJ. Effects of acute paroxetine administration on tryptophan metabolism and disposition in the rat. Br J Pharmacol 1991;102(2):429–33. [8] Badawy AA-B. The acute effects of lofepramine and desmethylimpramine on tryptophan metabolism and disposition in the rat. Br J Pharmacol 1986;89:859P. [9] Bonney EA, Matzinger P. Much IDO about Pregnancy. Nat Med 1998;4: 1128–9. [10] Ligam P, Manuelpillai U, Wallace EM, Walker D. Localisation of indoleamine 2,3-dioxygenase and kynurenine hydroxylase in the human placenta and decidua: implications for role of the kynurenine pathway in pregnancy. Placenta 2005;26(6):498–504. [11] Munn DH. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 1998;281(5380):1191–3.
Alok Banga Division of Child and Adolescent Psychiatry, Department of Psychiatry, University of Connecticut School of Medicine and Health Care, Farmington, CT, USA Venkatesh Handratta1 Division of Child and Adolescent Psychiatry, Department of Psychiatry, University of Connecticut School of Medicine and Health Care, 263 Farmington Avenue, Farmington, CT 06030, USA Tel.: +1 8606792730; fax: +1 8606701296 Lobna Ibrahim NIMH, USA Daniel F. Connor Division of Child and Adolescent Psychiatry, Department of Psychiatry, University of Connecticut School of Medicine and Health Care, Farmington, CT, USA doi:10.1016/j.mehy.2011.05.023 1
He is currently in community practice in Maryland, USA.
Reprogramming neurons by microRNAs into iPSCs to treat Parkinson’s disease
Sir, Parkinson’s disease (PD) is the second most common neurodegenerative disease. Cell replacement therapy has been tested clinically in PD. But, only embryonic stem cells (ESCs) can migrate to the damaged regions of brain tissue, engraft, and differentiate [1]. Due to ethical debate about ESCs, researchers developed a technique that reprograms cells into induced pluripotent stem cells (iPSCs) through viral expression of four transcription factors [2]. However, one important limiting factor for clinical application of iPSCs is the presence of viral vectors [3]. Recently, it has demonstrated that miRNAs do function in the reprogramming cells [4]. Nevertheless, transplantation of exogenous iPSCs carries some limitations, e.g., the immunocompatibility issues, survival, and progression of disease in the transplanted tissue [5]. Here, we hypothesized that an efficient microRNAs-based delivery system could induce iPSCs into the striatum and/or substantia nigra. For endogenous replacement, it should be noted that teratoma formation is an inherent feature of iPSCs. As this tumorigenic activity is lost following differentiation, pharmacological approaches, and genetic manipulation can be adopted to promote the neural differentiation. Finally, careful physiological evaluations are required to confirm the same function of new dopaminergic neurons. Hopefully, these invivo patient-specific iPSCs can bring a new avenue for cell replacement therapies. References [1] Srivastava AS, Shenouda S, Mishra R, Carrier E. Transplanted embryonic stem cells successfully survive, proliferate, and migrate to damaged regions of the mouse brain. Stem Cells 2006;24:1689–94. [2] Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006;126:663–76.