miR-196a provides antioxidative neuroprotection via USP15/Nrf2 regulation in Huntington's disease.

Huntington's disease (HD) is a devastating neurodegenerative disorder characterized by the accumulation of mutant Huntingtin protein (mHTT) and oxidative stress-induced neuronal damage. Based on previous reports, microRNA-196a (miR-196a) has emerged as a potential therapeutic target due to its neuroprotective effects in various neurodegenerative diseases. However, whether miR-196a functions through antioxidative effects is still unknown. In this study, we demonstrated that HD models, both in vitro and in vivo, exhibit elevated levels of reactive oxygen species (ROS) and increased neuronal death, and miR-196a mitigates ROS levels and reduces cell death in HD cells. Moreover, we elucidated that miR-196a facilitates the translocation of nuclear factor erythroid 2 (Nrf2) into the nucleus, enhancing the transcription of antioxidant genes, including heme oxygenase-1 (HO-1). We further identified ubiquitin-specific peptidase 15 (USP15), a direct target of miR-196a related to the Nrf2 pathway, and USP15 exacerbates mHTT aggregate formation while partially counteracting miR-196a-induced reductions in mHTT levels. Taken together, these findings shed light on the multifaceted role of miR-196a in HD, highlighting its potential as a therapeutic avenue for ameliorating oxidative stress and neurodegeneration in this debilitating disease.

miR-196a enhances polymerization of neuronal microfilaments through suppressing IMP3 and upregulating IGF2 in Huntington's disease.

Huntington's disease (HD) is one of the inheritable neurodegenerative diseases, and these diseases share several similar pathological characteristics, such as abnormal neuronal morphology. miR-196a is a potential target to provide neuroprotective functions, and has been reported to enhance polymerization of neuronal microtubules in HD. While microtubules and microfilaments are two important components of the neuronal cytoskeleton, whether miR-196a improves neuronal microfilaments is still unknown. Here, we identify insulin-like growth factor 2 mRNA binding protein 3 (IMP3), and show that miR-196a directly suppresses IMP3 to increase neurite outgrowth in neurons. In addition, IMP3 disturbs neurite outgrowth in vitro and in vivo, and worsens the microfilament polymerization. Moreover, insulin-like growth factor-II (IGF2) is identified as the downstream target of IMP3, and miR-196a downregulates IMP3 to upregulate IGF2, which increases microfilamental filopodia numbers and activates Cdc42 to increase neurite outgrowth. Besides, miR-196a increases neurite outgrowth through IGF2 in different HD models. Finally, higher expression of IMP3 and lower expression IGF2 are observed in HD transgenic mice and patients, and increase the formation of aggregates in the HD cell model. Taken together, miR-196a enhances polymerization of neuronal microfilaments through suppressing IMP3 and upregulating IGF2 in HD, supporting the neuroprotective functions of miR-196a through neuronal cytoskeleton in HD.

The regulatory roles of microRNAs toward pathogenesis and treatments in Huntington's disease.

Huntington's disease (HD) is one of neurodegenerative diseases, and is defined as a monogenetic disease due to the mutation of Huntingtin gene. This disease affects several cellular functions in neurons, and further influences motor and cognitive ability, leading to the suffering of devastating symptoms in HD patients. MicroRNA (miRNA) is a non-coding RNA, and is responsible for gene regulation at post-transcriptional levels in cells. Since one miRNA targets to several downstream genes, it may regulate different pathways simultaneously. As a result, it raises a potential therapy for different diseases using miRNAs, especially for inherited diseases. In this review, we will not only introduce the update information of HD and miRNA, but also discuss the development of potential miRNA-based therapy in HD. With the understanding toward the progression of miRNA studies in HD, we anticipate it may provide an insight to treat this devastating disease, even applying to other genetic diseases.

Fibroblast Growth Factor 9 Stimulates Neuronal Length Through NF-kB Signaling in Striatal Cell Huntington's Disease Models.

Proper development of neuronal cells is important for brain functions, and impairment of neuronal development may lead to neuronal disorders, implying that improvement in neuronal development may be a therapeutic direction for these diseases. Huntington's disease (HD) is a neurodegenerative disease characterized by impairment of neuronal structures, ultimately leading to neuronal death and dysfunctions of the central nervous system. Based on previous studies, fibroblast growth factor 9 (FGF9) may provide neuroprotective functions in HD, and FGFs may enhance neuronal development and neurite outgrowth. However, whether FGF9 can provide neuronal protective functions through improvement of neuronal morphology in HD is still unclear. Here, we study the effects of FGF9 on neuronal length in HD and attempt to understand the related working mechanisms. Taking advantage of striatal cell lines from HD knock-in mice, we found that FGF9 increases total neuronal length and upregulates several structural and synaptic proteins under HD conditions. In addition, activation of nuclear factor kappa B (NF-kB) signaling by FGF9 was observed to be significant in HD cells, and blockage of NF-kB leads to suppression of these structural and synaptic proteins induced by FGF9, suggesting the involvement of NF-kB signaling in these effects of FGF9. Taken these results together, FGF9 may enhance total neuronal length through upregulation of NF-kB signaling, and this mechanism could serve as an important mechanism for neuroprotective functions of FGF9 in HD.

FGF9 induces neurite outgrowth upon ERK signaling in knock-in striatal Huntington's disease cells.

AIMS: Huntington's disease (HD) is a neurodegenerative disease that causes deficits in neurite outgrowth, which suggests that enhancement of neurite outgrowth is a potential direction by which to improve HD. Our previous publications showed that fibroblast growth factor 9 (FGF9) provides anti-apoptosis and anti-oxidative functions in striatal cell models of HD through the extracellular signal-regulated kinases (ERK) pathway, and FGF9 also stimulates cytoskeletons to enhance neurite outgrowth via nuclear factor kappa B (NF-kB) signaling. In this study, we further demonstrate the importance of the ERK pathway for the neurite outgrowth induced by FGF9 in HD striatal models. MATERIALS AND METHODS: FGF9 was treated with ERK (U0126) or NF-kB (BAY11-7082) inhibitors in STHdhQ7/Q7 and STHdhQ111/Q111 striatal knock-in cell lines to examine neurite outgrowth, cytoskeletal markers, and synaptic proteins via immunofluorescence staining and Western blotting. NF-kB activity was analyzed by NF-kB promoter reporter assay. KEY FINDINGS: Here, we show that suppression of ERK signaling significantly inhibits FGF9-induced neurite outgrowth, cytoskeletal markers, and synaptic proteins in HD striatal cells. In addition, we also show suppression of ERK signaling significantly decreases FGF9-induced NF-kB activation, whereas suppression of NF-kB does not decrease FGF9-induced ERK signaling. These results suggest that FGF9 activates ERK signaling first, stimulates NF-kB upregulation, and then enhances neurite outgrowth in HD striatal cells. SIGNIFICANCE: We elucidate the more detailed mechanisms of neurite outgrowth enhanced by FGF9 in these HD striatal cells. This study may provide insights into targeting neurite outgrowth for HD therapy.

Fibroblast growth factor 9 activates anti-oxidative functions of Nrf2 through ERK signalling in striatal cell models of Huntington's disease.

Huntington's disease (HD) is a heritable neurodegenerative disorder, and has been characterized as an increase of oxidative stress in brain regions. In our previous results, we showed fibroblast growth factor 9 (FGF9) provides neuroprotective functions to suppress cell death in HD striatal cells dominantly through ERK signalling. However, whether the working mechanism of FGF9 is related to anti-oxidative stress in HD is still unknown. In this study, STHdhQ7/Q7 (Q7) and STHdhQ111/Q111 (Q111) striatal knock-in cell lines were used to examine the neuroprotective effects of FGF9 against oxidative stress in HD. Results show that FGF9 alleviates oxidative stress induced by starvation in Q7 and Q111 cells. The treatment of FGF9 not only induces upregulation and activation of nuclear factor erythroid 2-like 2 (Nrf2), a critical transcription factor for anti-oxidative stress, but also further upregulates its downstream targets, such as superoxide dismutase 2, gamma-glutamylcysteine synthetase and glutathione reductase. Furthermore, blockage of the Nrf2 pathway abolishes the anti-oxidative functions of FGF9, and inhibition of ERK signalling reduces the activation of the FGF9-Nrf2 pathway, resulting in higher level of oxidative stress in HD cells. These results support the neuroprotective effects of FGF9 against oxidative stress through the ERK-Nrf2 pathway, and imply one of potential strategies for therapy of HD.

Fibroblast Growth Factor 9 Suppresses Striatal Cell Death Dominantly Through ERK Signaling in Huntington's Disease.

BACKGROUND/AIMS: Huntington's disease (HD) is a heritable neurodegenerative disorder, and there is no cure for HD to date. A type of fibroblast growth factor (FGF), FGF9, has been reported to play prosurvival roles in other neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. However, the effects of FGF9 on HD is still unknown. With many similarities in the cellular and pathological mechanisms that eventually cause cell death in neurodegenerative diseases, we hypothesize that FGF9 might provide neuroprotective functions in HD. METHODS: In this study, STHdhQ7/Q7 (WT) and STHdhQ111/Q111 (HD) striatal knock-in cell lines were used to evaluate the neuroprotective effects of FGF9. Cell proliferation, cell death and neuroprotective markers were determined via the MTT assay, propidium iodide staining and Western blotting, respectively. The signaling pathways regulated by FGF9 were demonstrated using Western blotting. Additionally, HD transgenic mouse models were used to further confirm the neuroprotective effects of FGF9 via ELISA, Western blotting and immunostaining. RESULTS: Results show that FGF9 not only enhances cell proliferation, but also alleviates cell death as cells under starvation stress. In addition, FGF9 significantly upregulates glial cell line-derived neurotrophic factor (GDNF) and an anti-apoptotic marker, Bcl-xL, and decreases the expression level of an apoptotic marker, cleaved caspase 3. Furthermore, FGF9 functions through ERK, AKT and JNK pathways. Especially, ERK pathway plays a critical role to influence the effects of FGF9 toward cell survival and GDNF production. CONCLUSIONS: These results not only show the neuroprotective effects of FGF9, but also clarify the critical mechanisms in HD cells, further providing an insight for the therapeutic potential of FGF9 in HD.

miR-196a Enhances Neuronal Morphology through Suppressing RANBP10 to Provide Neuroprotection in Huntington's Disease.

MicroRNAs (miRNAs) play important roles in several neurobiological processes, including the development and progression of diseases. Previously, we identified that one specific miRNA, miR-196a, provides neuroprotective effects on Huntington's disease (HD), although the detailed mechanism is still unclear. Based on our bioinformatic analyses, we hypothesize miR-196a might offer neuroprotective functions through improving cytoskeletons of brain cells. Here, we show that miR-196a could enhance neuronal morphology, further ameliorating intracellular transport, synaptic plasticity, neuronal activity, and learning and memory abilities. Additionally, we found that miR-196a could suppress the expression of RAN binding protein 10 (RANBP10) through binding to its 3' untranslated region, and higher expression of RANBP10 exacerbates neuronal morphology and intracellular transport. Furthermore, miR-196a enhances neuronal morphology through suppressing RANBP10 and increasing the ability of ß-tubulin polymerization. Most importantly, we observed higher expression of RANBP10 in the brains of HD transgenic mice, and higher expression of RANBP10 might exacerbate the pathological aggregates in HD. Taken together, we provide evidence that enhancement of neuronal morphology through RANBP10 is one of the neuroprotective mechanisms for miR-196a. Since miR-196a has also been reported in other neuronal diseases, this study might offer insights with regard to the therapeutic use of miR-196a in other neuronal diseases.

The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models.

Spinocerebellar ataxia type 3 (SCA3), known as Machado-Joseph disease, is an autosomal dominant disease caused by an abnormal expansion of polyglutamine in ATXN3 gene, leading to neurodegeneration in SCA3 patients. Similar to other neurodegenerative diseases, the dysfunction of mitochondria is observed to cause neuronal death in SCA3 patients. Based on previous studies, proteolytic cleavage of mutant ATXN3 is found to produce truncated C-terminal fragments in SCA3 models. However, whether these truncated mutant fragments disturb mitochondrial functions and result in pathological death is still unclear. Here, we used neuroblastoma cell and transgenic mouse models to examine the effects of truncated mutant ATXN3 on mitochondria functions. In different models, we observed truncated mutant ATXN3 accelerated the formation of aggregates, which translocated into the nucleus to form intranuclear aggregates. In addition, truncated mutant ATXN3 caused more mitochondrial fission, and decreased the expression of mitochondrial fusion markers, including Mfn-1 and Mfn-2. Furthermore, truncated mutant ATXN3 decreased the mitochondrial membrane potential, increased reactive oxygen species and finally increased cell death rate. In transgenic mouse models, truncated mutant ATXN3 also led to more mitochondrial dysfunction, neurodegeneration and cell death in the cerebellums. This study supports the toxic fragment hypothesis in SCA3, and also provides evidence that truncated mutant ATXN3 is severer than full-length mutant one in vitro and in vivo.

Lentiviral transgenesis in mice via a simple method of viral concentration.

Transgenic animals are important in vivo models for biological research. However, low transgenic rates are commonly reported in the literature. Lentiviral transgenesis is a promising method that has greater efficiency with regard to generating transgenic animals, although the transgenic rate of this approach is highly dependent on different transgenes and concentrated lentiviruses. In this study, we modified a method to concentrate lentiviruses using a table centrifuge, commonly available in most laboratories, and carried out analysis of the transgenic efficiency in mice. Based on 26 individual constructs and 627 live pups, we found that the overall transgenic rate was more than 30%, which is higher than obtained with pronuclear microinjection. In addition, we did not find any significant differences in transgenic efficiency when the size of inserts was less than 5000 bp. These results not only show that our modified method can successfully generate transgenic mice but also suggest that this approach could be generally applied to different constructs when the size of inserts is less than 5000 bp. It is anticipated that the results of this study can help encourage the wider laboratory use of lentiviral transgenesis in mice.

Stem cell transplantation therapy in Parkinson's disease.

Ineffective therapeutic treatments and inadequate repair ability in the central nervous system are disturbing problems for several neurological diseases. Fortunately, the development of clinically applicable populations of stem cells has provided an avenue to overcome the failure of endogenous repair systems and substitute new cells into the damaged brain. However, there are still several existing obstacles to translating into clinical application. Here we review the stem-cell based therapies for Parkinson's disease and discuss the potential advantages and drawbacks. We hope this review may provide suggestions for viable strategies to overcome the current technical and biological issues associated with the application of stem cells in Parkinson's disease.

The Potential Regulatory Mechanisms of miR-196a in Huntington's Disease through Bioinformatic Analyses.

High throughput screening is a powerful tool to identify the potential candidate molecules involved during disease progression. However, analysis of complicated data is one of the most challenging steps on the way to obtaining useful results from this approach. Previously, we showed that a specific miRNA, miR-196a, could ameliorate the pathological phenotypes of Huntington's disease (HD) in different models, and performed high throughput screening by using the striatum of transgenic mice. In this study, we further tried to identify the potential regulatory mechanisms using different bioinformatic tools, including Database for Annotation, Visualization and Integrated Discovery (DAVID), Molecular Signatures Database (MSigDB), TargetScan and MetaCore. The results showed that miR-196a dominantly altered "ABC transporters", "RIG-I-like receptor signaling pathway", immune system", "adaptive immune system","tissue remodeling and wound repair" and "cytoskeleton remodeling". In addition, miR-196a also changed the expression of several well-defined pathways of HD, such as apoptosis and cell adhesion. Since these analyses showed the regulatory pathways are highly related to the modification of the cytoskeleton, we further confirmed that miR-196a could enhance the neurite outgrowth in neuroblastoma cells, suggesting miR-196a might provide beneficial functions through the alteration of cytoskeleton structures. Since impairment of the cytoskeleton has been reported in several neuronal diseases, this study will provide not only the potential working mechanisms of miR-196a but also insights for therapeutic strategies for use with different neuronal diseases.

The Differential Profiling of Ubiquitin-Proteasome and Autophagy Systems in Different Tissues before the Onset of Huntington's Disease Models.

Huntington's disease (HD) is a genetic and neurodegenerative disease, leading to motor and cognitive dysfunction in HD patients. At cellular level, this disease is caused by the accumulation of mutant huntingtin (HTT) in different cells, and finally results in the dysfunction of different cells. To clean these mutant proteins, ubiquitin-proteasome system (UPS) and autophagy system are two critical pathways in the brain; however, little is known in other peripheral tissues. As mutant HTT affects different tissues progressively and might influence the UPS and autophagy pathways at early stages, we attempted to examine two clearance systems in HD models before the onset. Here, in vitro results showed that the accumulation of UPS signals with time was observed obviously in neuroblastoma and kidney cells, not in other cells. In HD transgenic mice, we observed the impairment of UPS, but not autophagy, over time in the cortex and striatum. In heart and muscle tissues, disturbance of autophagy was observed, whereas dysfunction of UPS was displayed in liver and lung. These results suggest that two protein clearance pathways are disturbed differentially in different tissues before the onset of HD, and enhancement of protein clearance at early stages might provide a potential stratagem to alleviate the progression of HD.

Longitudinal monitoring of stem cell grafts in vivo using magnetic resonance imaging with inducible maga as a genetic reporter.

PURPOSE: The ability to longitudinally monitor cell grafts and assess their condition is critical for the clinical translation of stem cell therapy in regenerative medicine. Developing an inducible genetic magnetic resonance imaging (MRI) reporter will enable non-invasive and longitudinal monitoring of stem cell grafts in vivo. METHODS: MagA, a bacterial gene involved in the formation of iron oxide nanocrystals, was genetically modified for in vivo monitoring of cell grafts by MRI. Inducible expression of MagA was regulated by a Tet-On (Tet) switch. A mouse embryonic stem cell-line carrying Tet-MagA (mESC-MagA) was established by lentivirus transduction. The impact of expressing MagA in mESCs was evaluated via proliferation assay, cytotoxicity assay, teratoma formation, MRI, and inductively coupled plasma atomic emission spectroscopy (ICP-OES). Mice were grafted with mESCs with and without MagA (mESC-MagA and mESC-WT). The condition of cell grafts with induced "ON" and non-induced "OFF" expression of MagA was longitudinally monitored in vivo using a 7T MRI scanner. After imaging, whole brain samples were harvested for histological assessment. RESULTS: Expression of MagA in mESCs resulted in significant changes in the transverse relaxation rate (R2 or 1/T2) and susceptibility weighted MRI contrast. The pluripotency of mESCs carrying MagA was not affected in vitro or in vivo. Intracranial mESC-MagA grafts generated sufficient T2 and susceptibility weighted contrast at 7T. The mESC-MagA grafts can be monitored by MRI longitudinally upon induced expression of MagA by administering doxycycline (Dox) via diet. CONCLUSION: Our results demonstrate MagA could be used to monitor cell grafts noninvasively, longitudinally, and repetitively, enabling the assessment of cell graft conditions in vivo.

miR-196a ameliorates phenotypes of Huntington disease in cell, transgenic mouse, and induced pluripotent stem cell models.

Huntington disease (HD) is a dominantly inherited neurodegenerative disorder characterized by dysregulation of various genes. Recently, microRNAs (miRNAs) have been reported to be involved in this dysregulation, suggesting that manipulation of appropriate miRNA regulation may have a therapeutic benefit. Here, we report the beneficial effects of miR-196a (miR196a) on HD in cell, transgenic mouse models, and human induced pluripotent stem cells derived from one individual with HD (HD-iPSCs). In the in vitro results, a reduction of mutant HTT and pathological aggregates, accompanying the overexpression of miR-196a, was observed in HD models of human embryonic kidney cells and mouse neuroblastoma cells. In the in vivo model, HD transgenic mice overexpressing miR-196a revealed the suppression of mutant HTT in the brain and also showed improvements in neuropathological progression, such as decreases of nuclear, intranuclear, and neuropil aggregates and late-stage behavioral phenotypes. Most importantly, miR-196a also decreased HTT expression and pathological aggregates when HD-iPSCs were differentiated into the neuronal stage. Mechanisms of miR-196a in HD might be through the alteration of ubiquitin-proteasome systems, gliosis, cAMP response element-binding protein pathway, and several neuronal regulatory pathways in vivo. Taken together, these results show that manipulating miR-196a provides beneficial effects in HD, suggesting the potential therapeutical role of miR-196a in HD.

Significantly differential diffusion of neuropathological aggregates in the brain of transgenic mice carrying N-terminal mutant huntingtin fused with green fluorescent protein.

Huntington's disease (HD) is a genetically neurodegenerative disease, affecting the central nervous system and leading to mental and motor dysfunctions. To date, there is no cure for HD; as a result, HD patients gradually suffer devastating symptoms, such as chorea, weight loss, depression and mood swings, until death. According to previous studies, the exon 1 region of the huntingtin (HTT) gene with expanded CAG trinucleotide repeats plays a critical role in causing HD. In vitro studies using exon 1 of HTT fused with green fluorescent protein (GFP) gene have facilitated discovering several mechanisms of HD. However, whether this chimera construct exerts similar functions in vivo is still not clear. Here, we report the generation of transgenic mice carrying GFP fused with mutant HTT exon 1 containing 84 CAG trinucleotide repeats, and the evaluation of phenotypes via molecular, neuropathological and behavioral analyses. Results show that these transgenic mice not only displayed neuropathological characteristics, observed either by green fluorescent signals or by immunohistochemical staining, but also progressively developed pathological and behavioral symptoms of HD. Most interestingly, these transgenic mice showed significantly differential expression levels of nuclear aggregates between cortex and striatum regions, highly mimicking selective expression of mutant HTT in HD patients. To the best of our knowledge, this is the first report showing different nuclear diffusion profiling in mouse models with transgenic mice carrying the exon 1 region of mutant HTT. Our model will be beneficial for tracing the expression of mutant HTT and accelerating the understanding of selective pathological progression in HD.

Overexpression of Smad proteins, especially Smad7, in oral epithelial dysplasias.

OBJECTIVE: Transforming growth factor ß, via membrane-bound receptors and downstream Smad2-4, 7, can modulate tumorigenesis. Smad2 and Smad3 heterodimerize with Smad4, and the complex migrates to the nucleus to regulate the expression of target genes. Smad7 is a key negative regulator of this signaling pathway. This study aimed to examine Smad2-4, 7 expression and phosphorylated Smad2-3 (p-Smad2-3) in oral epithelial dysplasia and compared it with normal oral mucosa, hyperkeratosis/epithelial hyperplasia and squamous cell carcinoma (SCC). MATERIALS AND METHODS: Immunohistochemical staining of Smad2-4, 7 and p-Smad2-3, was performed for 75 samples of human oral mucosa, including hyperkeratosis/epithelial hyperplasia (n = 20), mild epithelial dysplasia (n = 11), moderate to severe epithelial dysplasia (n = 11), and SCC (n = 43). Normal buccal mucosa samples (n = 9) were also included. RESULTS: A significant increase in Smad7 expression was observed in the ascending order of samples of normal oral mucosa, hyperkeratosis/epithelial hyperplasia/mild oral epithelial dysplasia, moderate to severe oral epithelial dysplasia, and well-differentiated oral SCC/moderately to poorly differentiated oral SCC. Additionally, significant increases in Smad7 expression were noted as compared with expression of Smad2-4 and p-Smad2-3 in lesions of hyperkeratosis/epithelial hyperplasia, mild oral epithelial dysplasia, moderate to severe oral epithelial dysplasia, well-differentiated oral SCC, and moderately to poorly differentiated oral SCC. CONCLUSIONS: Our results indicate that Smad proteins, particularly Smad7, in oral epithelial dysplasia and SCC could contribute to the attenuation of Smads anti-proliferative signaling in cancer development. CLINICAL RELEVANCE: Smad7 could be a marker for risk of malignant transformation of oral epithelial dysplasia.

Characterization of dental pulp stem/stromal cells of Huntington monkey tooth germs.

BACKGROUND: Dental pulp stem/stromal cells (DPSCs) are categorized as adult stem cells (ASCs) that retain multipotent differentiation capabilities. DPSCs can be isolated from individuals at any age and are considered to be true personal stem cells, making DPSCs one of the potential options for stem cell therapy. However, the properties of DPSCs from individuals with an inherited genetic disorder, such as Huntington's disease (HD), have not been fully investigated. RESULTS: To examine if mutant huntingtin (htt) protein impacts DPSC properties, we have established DPSCs from tooth germ of transgenic monkeys that expressed both mutant htt and green fluorescent protein (GFP) genes (rHD/G-DPSCs), and from a monkey that expressed only the GFP gene (rG-DPSCs), which served as a control. Although mutant htt and oligomeric htt aggregates were overtly present in rHD/G-DPSCs, all rHD/G-DPSCs and rG-DPSCs shared similar characteristics, including self-renewal, multipotent differentiation capabilities, expression of stemness and differentiation markers, and cell surface antigen profile. CONCLUSIONS: Our results suggest that DPSCs from Huntington monkeys retain ASC properties. Thus DPSCs derived from individuals with genetic disorders such as HD could be a potential source of personal stem cells for therapeutic purposes.

Reprogramming Huntington monkey skin cells into pluripotent stem cells.

Induced pluripotent Huntington's disease monkey stem cells (rHD-iPSCs) were established by the overexpression of rhesus macaque transcription factors (Oct4, Sox2, and Klf4) in transgenic Huntington's monkey skin fibroblasts. The rHD-iPSCs were pluripotent and capable of differentiating into neuronal cell types in vitro and developed teratoma in immune compromised mice. We also demonstrated the upregulation of endogenous Oct4 and Sox2 after successful reprogramming to pluripotency in rHD-iPSCs, which was not expressed in skin fibroblasts. rHD-iPSCs also developed cellular features comparable to Huntington's disease (HD), including the accumulation of mutant huntingtin (htt) aggregate and the formation of intranuclear inclusions (NIs) paralleling neural differentiation in vitro. Induced pluripotent stem cells from transgenic HD monkeys open a new era of nonhuman primate modeling of human diseases. rHD-iPSCs that develop key HD cellular features and parallel neural differentiation can be a powerful platform for investigating the developmental impact on HD pathogenesis and developing new therapies, which can be evaluated in HD monkeys from whom the rHD-iPSCs were derived.