Cell transplantation therapy using human pluripotent stem cell (PSC)–derived midbrain dopaminergic (mDA) neurons is soon expected to be available for patients with Parkinson's disease (PD). Highly efficient and reproducible protocols for the induction of mDA neurons for clinical application have already been reported, and the therapeutic potential and safety of these cells have been studied in parkinsonian animal models as preclinical trials. However, a new strategy that improves the survival and functional quality of the grafted mDA neurons is needed to achieve maximal efficacy of the cell transplantation therapy. One strategy would definitively be to adapt the brain's microenvironment with the use of small compounds, such as soluble factors and clinical drugs, in addition to current pharmacotherapies for PD. In this mini review, we focus on recent findings regarding the induction of mDA neurons from human PSCs toward clinical application and on a complementary strategy of drug treatment toward more efficient cell transplantation therapy for PD patients. In context Parkinson’s disease (PD) is a common neurodegenerative disorder that is characterized by the selective degeneration of midbrain dopaminergic (mDA) neurons. The loss of mDA neurons causes resting tremor, rigidity, bradykinesia, gait disturbances, and postural instability. Earlier, the main treatment for PD was pharmacotherapy using levodopa and dopamine receptor agonists. The efficacy of pharmacotherapy is gradually lost during long-term treatment, however, and side effects, such as the on–off phenomenon, wearing-off phenomenon, and drug-induced dyskinesia, begin to appear in later stages. In addition, pharmacotherapy cannot recover the lost mDA neurons. Therefore, cell transplantation therapy, which originally used aborted human embryonic tissue but has now expanded to other pluripotent stem cells (PSCs) sources, was developed to restore the lost mDA neurons in PD patients as a therapeutic option. In this study, we review recent progress in cell transplantation therapies and examine how drug treatment can improve PD patient outcome.
{"title":"Drug discovery toward successful cell transplantation therapy for Parkinson's disease using human pluripotent stem cells","authors":"Kaneyasu Nishimura, J. Takahashi","doi":"10.3402/arb.v3.31772","DOIUrl":"https://doi.org/10.3402/arb.v3.31772","url":null,"abstract":"Cell transplantation therapy using human pluripotent stem cell (PSC)–derived midbrain dopaminergic (mDA) neurons is soon expected to be available for patients with Parkinson's disease (PD). Highly efficient and reproducible protocols for the induction of mDA neurons for clinical application have already been reported, and the therapeutic potential and safety of these cells have been studied in parkinsonian animal models as preclinical trials. However, a new strategy that improves the survival and functional quality of the grafted mDA neurons is needed to achieve maximal efficacy of the cell transplantation therapy. One strategy would definitively be to adapt the brain's microenvironment with the use of small compounds, such as soluble factors and clinical drugs, in addition to current pharmacotherapies for PD. In this mini review, we focus on recent findings regarding the induction of mDA neurons from human PSCs toward clinical application and on a complementary strategy of drug treatment toward more efficient cell transplantation therapy for PD patients. In context Parkinson’s disease (PD) is a common neurodegenerative disorder that is characterized by the selective degeneration of midbrain dopaminergic (mDA) neurons. The loss of mDA neurons causes resting tremor, rigidity, bradykinesia, gait disturbances, and postural instability. Earlier, the main treatment for PD was pharmacotherapy using levodopa and dopamine receptor agonists. The efficacy of pharmacotherapy is gradually lost during long-term treatment, however, and side effects, such as the on–off phenomenon, wearing-off phenomenon, and drug-induced dyskinesia, begin to appear in later stages. In addition, pharmacotherapy cannot recover the lost mDA neurons. Therefore, cell transplantation therapy, which originally used aborted human embryonic tissue but has now expanded to other pluripotent stem cells (PSCs) sources, was developed to restore the lost mDA neurons in PD patients as a therapeutic option. In this study, we review recent progress in cell transplantation therapies and examine how drug treatment can improve PD patient outcome.","PeriodicalId":269533,"journal":{"name":"Advances in Regenerative Biology","volume":"71 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127393522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
T he launch of Advances in Regenerative Biology deserves to be celebrated not only for being a promising new journal in an exciting field of the life sciences but also for adopting a notable approach of manuscript evaluation: double-blind peer review. This approach is primarily notable for its exceptional rarity in natural science journals, despite overwhelming support for it from the research community. Here, I summarise what in my view are the key advantages of double-blind peer review over the alternatives and discuss how research and researchers can benefit from its wider implementation. Three main systems of pre-publication peer review have been proposed, which differ with respect to whether the reviewers know the identity of the authors and vice versa: open, single-blind and double-blind. In open peer review both sides know who they are, in the single-blind system only the reviewers know the identities of the authors, whereas in the double-blind approach the identities of both sides are not revealed during the review process. The masking of author and reviewer identities is intended to minimise bias. For example, reviewers may be biased in evaluating the authors’ work based on who they are, where and with whom they work; similarly, authors disgruntled by critical reviews may be biased in their future interactions with the reviewers. There are some who would dispute that ‘serious’ scientists can have any bias at all, be it in their role as reviewers or as authors, but this can hardly be taken as anything more than wishful thinking. Bias is at the core of human nature. Indeed much of basic research methodology is designed to neutralise our inevitable biases in interpreting our data. Moreover, pervasive even if subtle and unconscious bias among researchers with respect to gender, race, country of origin or affiliation has been consistently documented (1 6). As long as research is carried out by humans, bias will be here to stay, and instead of denying it, we should try to reduce it. In doing so, there is no need to reinvent the wheel, as a gold standard approach for minimising bias in situations involving human interactions is well established: double blinding. For example, in a clinical trial setting, neither the doctors nor the patients know who belongs to the placebo control group and who gets the drug, impeding biased data reporting, collection or analysis. One might thus reasonably expect that a similar double-blind approach would be standard fare for the peer-review process. Indeed, in some branches of academia, such as the social sciences, double-blind peer review has become an accepted system perhaps because social scientists are better aware of the ubiquity and pitfalls of human bias. In the natural sciences, however, by far the dominant form of research evaluation is single-blind review, whereas the double-blind practice is exceedingly uncommon. So why is there such a profound rift between the way in which the ‘hard sciences’ are con
{"title":"Who stands to win from double-blind peer review?","authors":"B. Garvalov","doi":"10.3402/ARB.V2.26879","DOIUrl":"https://doi.org/10.3402/ARB.V2.26879","url":null,"abstract":"T he launch of Advances in Regenerative Biology deserves to be celebrated not only for being a promising new journal in an exciting field of the life sciences but also for adopting a notable approach of manuscript evaluation: double-blind peer review. This approach is primarily notable for its exceptional rarity in natural science journals, despite overwhelming support for it from the research community. Here, I summarise what in my view are the key advantages of double-blind peer review over the alternatives and discuss how research and researchers can benefit from its wider implementation. Three main systems of pre-publication peer review have been proposed, which differ with respect to whether the reviewers know the identity of the authors and vice versa: open, single-blind and double-blind. In open peer review both sides know who they are, in the single-blind system only the reviewers know the identities of the authors, whereas in the double-blind approach the identities of both sides are not revealed during the review process. The masking of author and reviewer identities is intended to minimise bias. For example, reviewers may be biased in evaluating the authors’ work based on who they are, where and with whom they work; similarly, authors disgruntled by critical reviews may be biased in their future interactions with the reviewers. There are some who would dispute that ‘serious’ scientists can have any bias at all, be it in their role as reviewers or as authors, but this can hardly be taken as anything more than wishful thinking. Bias is at the core of human nature. Indeed much of basic research methodology is designed to neutralise our inevitable biases in interpreting our data. Moreover, pervasive even if subtle and unconscious bias among researchers with respect to gender, race, country of origin or affiliation has been consistently documented (1 6). As long as research is carried out by humans, bias will be here to stay, and instead of denying it, we should try to reduce it. In doing so, there is no need to reinvent the wheel, as a gold standard approach for minimising bias in situations involving human interactions is well established: double blinding. For example, in a clinical trial setting, neither the doctors nor the patients know who belongs to the placebo control group and who gets the drug, impeding biased data reporting, collection or analysis. One might thus reasonably expect that a similar double-blind approach would be standard fare for the peer-review process. Indeed, in some branches of academia, such as the social sciences, double-blind peer review has become an accepted system perhaps because social scientists are better aware of the ubiquity and pitfalls of human bias. In the natural sciences, however, by far the dominant form of research evaluation is single-blind review, whereas the double-blind practice is exceedingly uncommon. So why is there such a profound rift between the way in which the ‘hard sciences’ are con","PeriodicalId":269533,"journal":{"name":"Advances in Regenerative Biology","volume":"103 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122298811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Considering the incidence of retinal pigment epithelium (RPE)-related blinding disease will grow to 200 million globally by 2020, the impact of restoring vision by successfully replacing failing or dying RPE is great. In spite of fervent efforts to use primary RPE as a source for transplantation for over 30 years, a clinical therapy has yet to be developed. Due to the progress of pluripotent stem cell technologies and development of RPE differentiation protocols, primary human RPE culture has largely been set aside as a source of RPE for transplantation, as human embryonic stem cell (hESC)- and induced pluripotent stem cell (hiPSC)-derived RPE have become the current popular source for transplantation. Recently, a series of seminal advances in human primary RPE culture has renewed an interest in their potential as a source for RPE transplantation. Primary RPE are better studied and understood than hESC/hiPSC-derived RPE, have an inherent lower risk of tumor formation, and can be Major Histocompatibility Complex (MHC) donor-matched, making them valuable candidates alongside pluripotent stem cells as sources for cell transplantation therapy for RPE-related eye diseases. In context Some of the most prevalent blinding diseases, including Age-related Macular Degeneration, Stargardt’s Disease, Retinitis Pigmentosa and others, affect a single epithelial layer in the back of the eye, called the retinal pigment epithelium (RPE). For over the past 40 years, much hope has rested in using adult RPE, for example isolated from cadaver donors, for transplantation, to replace the diseased RPE in affected patients. Critical barriers to this objective are 1. being able to isolate and grow RPE that maintain their physiological and morphological characteristics in vitro and 2. assure successful engraftment and survival of the transplanted cells. What we observed was that often, once dissected, RPE isolated from cadaver donor eyes would change their physiology and not maintain their RPE functions when cultured in vitro. Here we summarize new advances in using adult RPE, which have renewed their promise in treating RPE-related eye diseases.
{"title":"Adult human RPE for transplantation: renewing an old promise","authors":"Timothy A. Blenkinsop","doi":"10.3402/arb.v2.27144","DOIUrl":"https://doi.org/10.3402/arb.v2.27144","url":null,"abstract":"Considering the incidence of retinal pigment epithelium (RPE)-related blinding disease will grow to 200 million globally by 2020, the impact of restoring vision by successfully replacing failing or dying RPE is great. In spite of fervent efforts to use primary RPE as a source for transplantation for over 30 years, a clinical therapy has yet to be developed. Due to the progress of pluripotent stem cell technologies and development of RPE differentiation protocols, primary human RPE culture has largely been set aside as a source of RPE for transplantation, as human embryonic stem cell (hESC)- and induced pluripotent stem cell (hiPSC)-derived RPE have become the current popular source for transplantation. Recently, a series of seminal advances in human primary RPE culture has renewed an interest in their potential as a source for RPE transplantation. Primary RPE are better studied and understood than hESC/hiPSC-derived RPE, have an inherent lower risk of tumor formation, and can be Major Histocompatibility Complex (MHC) donor-matched, making them valuable candidates alongside pluripotent stem cells as sources for cell transplantation therapy for RPE-related eye diseases. In context Some of the most prevalent blinding diseases, including Age-related Macular Degeneration, Stargardt’s Disease, Retinitis Pigmentosa and others, affect a single epithelial layer in the back of the eye, called the retinal pigment epithelium (RPE). For over the past 40 years, much hope has rested in using adult RPE, for example isolated from cadaver donors, for transplantation, to replace the diseased RPE in affected patients. Critical barriers to this objective are 1. being able to isolate and grow RPE that maintain their physiological and morphological characteristics in vitro and 2. assure successful engraftment and survival of the transplanted cells. What we observed was that often, once dissected, RPE isolated from cadaver donor eyes would change their physiology and not maintain their RPE functions when cultured in vitro. Here we summarize new advances in using adult RPE, which have renewed their promise in treating RPE-related eye diseases.","PeriodicalId":269533,"journal":{"name":"Advances in Regenerative Biology","volume":"144 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131569533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
An interview with Dr. Masayo Takahashi, Head of the Laboratory for Retinal Regeneration at the RIKEN Center for Developmental Biology, Kobe, Japan. (Published: 11 February 2015) Citation: Advances in Regenerative Biology 2015, 2 : 27401 - http://dx.doi.org/10.3402/arb.v2.27401
采访日本神户理化研究所发育生物学中心视网膜再生实验室主任Masayo Takahashi博士。(发表于2015年2月11日)引用本文:Advances in Regenerative Biology 2015, 2: 27401 - http://dx.doi.org/10.3402/arb.v2.27401
{"title":"A regenerative chit-chat with Masayo Takahashi","authors":"M. Paterlini","doi":"10.3402/ARB.V2.27401","DOIUrl":"https://doi.org/10.3402/ARB.V2.27401","url":null,"abstract":"An interview with Dr. Masayo Takahashi, Head of the Laboratory for Retinal Regeneration at the RIKEN Center for Developmental Biology, Kobe, Japan. (Published: 11 February 2015) Citation: Advances in Regenerative Biology 2015, 2 : 27401 - http://dx.doi.org/10.3402/arb.v2.27401","PeriodicalId":269533,"journal":{"name":"Advances in Regenerative Biology","volume":"20 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"117189507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Osteogenesis imperfecta (OI) is a rare heritable disease characterized by skeletal fragility, bone deformity, and growth retardation. In its classical and more common forms, it is caused by dominant mutations in collagen type I genes, COL1A1 and COL1A2. A wide range of clinical severity is described in OI, ranging from very mild to moderately severe, progressively deforming, and perinatal lethal. Mutations causing null allele and consequent synthesis of half of the amount of normal collagen are responsible for milder OI phenotypes, whereas point mutations altering amino acid sequence, thus affecting protein structure, lead to severe OI outcomes. Because no resolutive cures are so far available for OI patients and given the new advances in gene-targeting technology, genetic and cellular therapy represent an appealing option for OI treatment. In this review, we briefly summarized what has been done so far for classical OI in terms of novel regenerative approaches. The different strategies adopted to silence the mutant allele with the aim of converting severe qualitative defects to milder quantitative ones, and for transplanting normal multipotent cells to generate a mosaic condition, which in OI is associated to lack of clinical symptoms, are presented. The key issues that still need to be addressed for the effective clinical application of these strategies are critically discussed.
{"title":"New frontiers for dominant osteogenesis imperfecta treatment: gene/cellular therapy approaches","authors":"R. Besio, A. Forlino","doi":"10.3402/arb.v2.27964","DOIUrl":"https://doi.org/10.3402/arb.v2.27964","url":null,"abstract":"Osteogenesis imperfecta (OI) is a rare heritable disease characterized by skeletal fragility, bone deformity, and growth retardation. In its classical and more common forms, it is caused by dominant mutations in collagen type I genes, COL1A1 and COL1A2. A wide range of clinical severity is described in OI, ranging from very mild to moderately severe, progressively deforming, and perinatal lethal. Mutations causing null allele and consequent synthesis of half of the amount of normal collagen are responsible for milder OI phenotypes, whereas point mutations altering amino acid sequence, thus affecting protein structure, lead to severe OI outcomes. Because no resolutive cures are so far available for OI patients and given the new advances in gene-targeting technology, genetic and cellular therapy represent an appealing option for OI treatment. In this review, we briefly summarized what has been done so far for classical OI in terms of novel regenerative approaches. The different strategies adopted to silence the mutant allele with the aim of converting severe qualitative defects to milder quantitative ones, and for transplanting normal multipotent cells to generate a mosaic condition, which in OI is associated to lack of clinical symptoms, are presented. The key issues that still need to be addressed for the effective clinical application of these strategies are critically discussed.","PeriodicalId":269533,"journal":{"name":"Advances in Regenerative Biology","volume":"77 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124524279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. S. Souza, B. Paulsen, S. Devalle, Silvia Lima Costa, H. Borges, S. Rehen
Flavonoids are polyphenolic compounds that are ubiquitous in plants and have biological effects on cancer cells and other cell types. In particular, apigenin (API) has been shown to bind to estrogen receptors, which affect the development, maturation, function, and plasticity of the nervous system. The aim of this study was to investigate the effects of 4′,5,7-trihydroxyflavone (API) upon the neural differentiation of human pluripotent stem cells. Treatment of both human embryonic stem cells and human induced pluripotent stem cells with API increased the number of nestin (NES+) neural progenitor cells compared to untreated controls. API also induced the expression of neuronal markers, such as β-tubulin-III (TUBB3), microtubule-associated protein 2 (MAP2), polysialylated-neural cell adhesion molecule (PSA-NCAM), synapsin 1 (SYN1), neurofilament (NEF), choline acetyltransferase (CHAT), glutamate decarboxylase (GAD1), and parvalbumin (PVALB) proteins. Antagonists of estrogen receptors (ESR1 and ESR2) suppressed the effects of API. API-induced differentiation was followed by increased expression of retinoic acid (RA) receptors (RARA and RARB) and retinoic X receptor (RXR) G, but not RARG1 or RXRB. Neural differentiation induced by API was drastically reduced by the inhibition of RARs. In addition, API also increased synaptogenesis in RA-differentiated neurons. These findings suggest that API induces neural differentiation of human pluripotent stem cells through estrogen receptor and RAR signaling and improves their functional differentiation into neurons.
黄酮类化合物是一种多酚类化合物，在植物中普遍存在，对癌细胞和其他类型的细胞有生物作用。特别是芹菜素(API)已被证明与雌激素受体结合，影响神经系统的发育、成熟、功能和可塑性。本研究旨在探讨4′，5,7-三羟基黄酮(API)对人多能干细胞神经分化的影响。与未处理的对照相比，用API处理的人胚胎干细胞和人诱导多能干细胞增加了巢蛋白(NES+)神经祖细胞的数量。API还诱导了神经元标志物的表达，如β-微管蛋白- iii (TUBB3)、微管相关蛋白2 (MAP2)、多唾液酸-神经细胞粘附分子(PSA-NCAM)、突触素1 (SYN1)、神经丝(NEF)、胆碱乙酰转移酶(CHAT)、谷氨酸脱羧酶(GAD1)和小白蛋白(PVALB)蛋白。雌激素受体(ESR1和ESR2)拮抗剂抑制API的作用。api诱导分化后，维甲酸(RA)受体(RARA和RARB)和维甲酸X受体(RXR) G的表达增加，但RARG1和RXRB的表达不增加。API诱导的神经分化由于RARs的抑制而明显减弱。此外，API还增加了ra分化神经元的突触发生。提示API通过雌激素受体和RAR信号通路诱导人多能干细胞神经分化，促进多能干细胞向神经元的功能分化。
{"title":"Commitment of human pluripotent stem cells to a neural lineage is induced by the pro-estrogenic flavonoid apigenin","authors":"C. S. Souza, B. Paulsen, S. Devalle, Silvia Lima Costa, H. Borges, S. Rehen","doi":"10.3402/arb.v2.29244","DOIUrl":"https://doi.org/10.3402/arb.v2.29244","url":null,"abstract":"Flavonoids are polyphenolic compounds that are ubiquitous in plants and have biological effects on cancer cells and other cell types. In particular, apigenin (API) has been shown to bind to estrogen receptors, which affect the development, maturation, function, and plasticity of the nervous system. The aim of this study was to investigate the effects of 4′,5,7-trihydroxyflavone (API) upon the neural differentiation of human pluripotent stem cells. Treatment of both human embryonic stem cells and human induced pluripotent stem cells with API increased the number of nestin (NES+) neural progenitor cells compared to untreated controls. API also induced the expression of neuronal markers, such as β-tubulin-III (TUBB3), microtubule-associated protein 2 (MAP2), polysialylated-neural cell adhesion molecule (PSA-NCAM), synapsin 1 (SYN1), neurofilament (NEF), choline acetyltransferase (CHAT), glutamate decarboxylase (GAD1), and parvalbumin (PVALB) proteins. Antagonists of estrogen receptors (ESR1 and ESR2) suppressed the effects of API. API-induced differentiation was followed by increased expression of retinoic acid (RA) receptors (RARA and RARB) and retinoic X receptor (RXR) G, but not RARG1 or RXRB. Neural differentiation induced by API was drastically reduced by the inhibition of RARs. In addition, API also increased synaptogenesis in RA-differentiated neurons. These findings suggest that API induces neural differentiation of human pluripotent stem cells through estrogen receptor and RAR signaling and improves their functional differentiation into neurons.","PeriodicalId":269533,"journal":{"name":"Advances in Regenerative Biology","volume":"8 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122307902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. Davies, C-Hong Chang, Melanie L. Lawrence, Christopher G Mills, J. Mullins
There is an urgent need for new ways to treat end-stage renal disease: by promoting regeneration in situ, by repopulating decellularized donor organs with a patient's own stem cells, or by making entirely new kidneys. There are two broad strategies for making new kidneys: precision engineering by positioning everything exactly – for example, by 3D printing – or supporting cells’ self-organizing ability. We describe the latter approach, which begins with a suspension of renogenic stem cells and produces a small kidney with nephrons, a collecting duct system, active transport, and an ability to integrate with host vasculature. Many problems have to be solved before these kidneys are directly clinically useful, including size, maturation, provision of a ureter, and production from human-induced pluripotent stem cells. Even the existing engineered kidneys, if they can be made from human rather than animal cells, may be useful for assays for adverse drug reactions that will be free of the problems of extrapolating from animal tests to predicted human responses.
{"title":"Engineered kidneys: principles, progress, and prospects","authors":"J. Davies, C-Hong Chang, Melanie L. Lawrence, Christopher G Mills, J. Mullins","doi":"10.3402/arb.v1.24990","DOIUrl":"https://doi.org/10.3402/arb.v1.24990","url":null,"abstract":"There is an urgent need for new ways to treat end-stage renal disease: by promoting regeneration in situ, by repopulating decellularized donor organs with a patient's own stem cells, or by making entirely new kidneys. There are two broad strategies for making new kidneys: precision engineering by positioning everything exactly – for example, by 3D printing – or supporting cells’ self-organizing ability. We describe the latter approach, which begins with a suspension of renogenic stem cells and produces a small kidney with nephrons, a collecting duct system, active transport, and an ability to integrate with host vasculature. Many problems have to be solved before these kidneys are directly clinically useful, including size, maturation, provision of a ureter, and production from human-induced pluripotent stem cells. Even the existing engineered kidneys, if they can be made from human rather than animal cells, may be useful for assays for adverse drug reactions that will be free of the problems of extrapolating from animal tests to predicted human responses.","PeriodicalId":269533,"journal":{"name":"Advances in Regenerative Biology","volume":"54 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2014-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122072609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In humans, chimerisms (Chs) can occur naturally or be induced through artificial means. Feto-maternal Chs are natural and result from the spontaneous trafficking of hematopoietic or other types of cells across the placenta during pregnancy. These Chs can be transient or persist for many years and even decades. Mixed hematopoietic Chs (MHChs) can also be artificially induced, and they might have profound effects on the modulation of the immune system, which can be used for inducing donor-specific tolerance in recipients of allogeneic organ transplantation. Nonetheless, the main obstacle for the establishment of such Chs is that they require the engraftment of donor hematopoietic cells, which at present can only be accomplished using relatively toxic regimens that preclude its widespread use and currently restricts its application to some special patients, in which both a solid organ (e.g. a renal allograft) and a marrow transplantation are necessary. However, it is likely that less toxic strategies are developed that can be clinically applicable in the next decade to induce tolerance in organ transplantation. A variant of Chs is the molecular Chs, in which a proportion of the hematopoietic cells would be transduced to express a transgene (e.g. encoding a therapeutic protein, an auto-antigen, or an allergen), so that specific tolerance to these molecules is induced. This might have therapeutic applications in fields such as replacement and genetic therapies, autoimmune diseases, or allergy.
{"title":"Hematopoietic chimerisms: friends or foes?","authors":"S. Casacuberta-Serra, L. Martorell, J. Barquinero","doi":"10.3402/arb.v1.24429","DOIUrl":"https://doi.org/10.3402/arb.v1.24429","url":null,"abstract":"In humans, chimerisms (Chs) can occur naturally or be induced through artificial means. Feto-maternal Chs are natural and result from the spontaneous trafficking of hematopoietic or other types of cells across the placenta during pregnancy. These Chs can be transient or persist for many years and even decades. Mixed hematopoietic Chs (MHChs) can also be artificially induced, and they might have profound effects on the modulation of the immune system, which can be used for inducing donor-specific tolerance in recipients of allogeneic organ transplantation. Nonetheless, the main obstacle for the establishment of such Chs is that they require the engraftment of donor hematopoietic cells, which at present can only be accomplished using relatively toxic regimens that preclude its widespread use and currently restricts its application to some special patients, in which both a solid organ (e.g. a renal allograft) and a marrow transplantation are necessary. However, it is likely that less toxic strategies are developed that can be clinically applicable in the next decade to induce tolerance in organ transplantation. A variant of Chs is the molecular Chs, in which a proportion of the hematopoietic cells would be transduced to express a transgene (e.g. encoding a therapeutic protein, an auto-antigen, or an allergen), so that specific tolerance to these molecules is induced. This might have therapeutic applications in fields such as replacement and genetic therapies, autoimmune diseases, or allergy.","PeriodicalId":269533,"journal":{"name":"Advances in Regenerative Biology","volume":"25 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2014-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126000335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. J. Mateos-Aierdi, A. Aiastui, M. Goicoechea, A. L. de Munain
Limb-girdle muscular dystrophies (LGMDs) comprise a heterogeneous group of genetically determined disorders in which degeneration of the skeletal muscle is prominent. As no efficient pharmacological therapies exist that are able to reverse the course of these diseases, alternative regenerative therapies based on cell transfer or gene transfer approaches have been developed. These latter therapies will be the topic of this mini-review. To date, recombinant adeno-associated viral vectors have been reported as the best available gene transfer vectors for gene therapies targeting skeletal muscle tissue, due to their high tropism for this tissue, long-term stability, and low immunogenicity, among other features. However, the fact that these vectors cannot package large gene sizes represents a hurdle for the treatment of LGMDs caused by defects in large genes. Preclinical studies based on the transfer of disease-causing genes or muscle regulator genes that could ameliorate the course of the disease have led to a few clinical trials in which safety and efficacy studies are currently being performed. However, important barriers such as difficulties in delivering the viral vectors through all the affected skeletal muscles, the degenerative stage of the muscle at the time of treatment, and the potential immune response against the protein encoded by the transferred gene need to be overcome in order to maximize the efficacy of the therapies and prevent the development of the diseases.
{"title":"Advances in gene therapies for limb-girdle muscular dystrophies","authors":"A. J. Mateos-Aierdi, A. Aiastui, M. Goicoechea, A. L. de Munain","doi":"10.3402/arb.v1.25048","DOIUrl":"https://doi.org/10.3402/arb.v1.25048","url":null,"abstract":"Limb-girdle muscular dystrophies (LGMDs) comprise a heterogeneous group of genetically determined disorders in which degeneration of the skeletal muscle is prominent. As no efficient pharmacological therapies exist that are able to reverse the course of these diseases, alternative regenerative therapies based on cell transfer or gene transfer approaches have been developed. These latter therapies will be the topic of this mini-review. To date, recombinant adeno-associated viral vectors have been reported as the best available gene transfer vectors for gene therapies targeting skeletal muscle tissue, due to their high tropism for this tissue, long-term stability, and low immunogenicity, among other features. However, the fact that these vectors cannot package large gene sizes represents a hurdle for the treatment of LGMDs caused by defects in large genes. Preclinical studies based on the transfer of disease-causing genes or muscle regulator genes that could ameliorate the course of the disease have led to a few clinical trials in which safety and efficacy studies are currently being performed. However, important barriers such as difficulties in delivering the viral vectors through all the affected skeletal muscles, the degenerative stage of the muscle at the time of treatment, and the potential immune response against the protein encoded by the transferred gene need to be overcome in order to maximize the efficacy of the therapies and prevent the development of the diseases.","PeriodicalId":269533,"journal":{"name":"Advances in Regenerative Biology","volume":"35 1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2014-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133148269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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