Skip to main content

Advertisement

  • Review
  • Open Access

Direct conversion from skin fibroblasts to functional dopaminergic neurons for biomedical application

Biomedical Dermatology20171:4

https://doi.org/10.1186/s41702-017-0004-5

©  The Author(s) 2017

  • Received: 24 January 2017
  • Accepted: 28 August 2017
  • Published:

Abstract

Recent progress in tissue engineering research led to the generation of different types of cells from a handful of skin tissue. Lineage reprogramming is a nascent field, which holds great potential to expand its use in regenerative medicine and disease modeling. The concept of somatic cell epigenetic stability has been fundamentally reshaped through the report of direct conversion of somatic identity to another lineage by introducing transcription factors. Here, we review recent advances in lineage reprogramming research, especially direct conversion into dopamine neurons from fibroblasts.

Keywords

  • Direct conversion
  • Dopamine neurons
  • Fibroblasts and iPSC

Background

Parkinson’s disease (PD) is a movement disorder that is caused by chronic and progressive degeneration of midbrain dopamine (mDA) neurons in substantia nigra of brain (de Lau and Breteler 2006; Betarbet et al. 2000). Because there is no cure for PD patients, researchers have developed alternative ways to cure PD using cell-based transplantation therapy (Barker et al. 2015; Olanow et al. 1996). Fetal cell transplantation demonstrated that cell-based transplantation therapy is a viable therapeutic approach, showing improvement of PD-related symptoms in some patients (Mendez et al. 2005; Li et al. 2008; Kordower et al. 1996; Kordower et al. 1998; Kordower et al. 2008; Hagell et al. 1999). However, there are significant shortcomings including ethical, technical, and practical issues, as well as variable ranges in effectiveness (Olanow et al. 2003; Freed et al. 2001). After introduction of induced pluripotent stem cell (iPSC) technology by Shinya Yamanaka and his colleagues a decade ago, patient-derived iPSCs have been extensively investigated to generate functional autologous mDA neurons for clinical and research use (Takahashi and Yamanaka 2006; Tapia and Scholer 2016; Takahashi and Yamanaka 2016; Li and Izpisua Belmonte 2016; Karagiannis and Eto 2016; Mertens et al. 2016; Hotta and Yamanaka 2015). Consequently, concept of iPSC generation that somatic tissues can be reprogrammed to early embryonic-like cells by transcription factors raised the question of whether transcription factors could reprogram somatic cell differentiation. This concept was originally demonstrated by the conversion of fibroblasts into myoblasts by introducing expressing plasmid containing MyoD (Davis et al. 1987). Subsequently, introduction of transcription factors induces direct conversion of different cell types: (1) glial cells into neuronal cells, (2) liver into pancreas, and (3) B cells into macrophages (Heins et al. 2002; Kulessa et al. 1995; Shen et al. 2000; Xie et al. 2004). Moreover, induction of neuronal cells from fibroblasts using defined transcription factors showed that the direct conversion could be manipulated across different germ layers (Vierbuchen et al. 2010). Transcription factors known to serve crucial roles in dopamine neuron specification and maturation are required for direct conversion of dopamine neurons from fibroblasts (Caiazzo et al. 2011; Pfisterer et al. 2011; Kim et al. 2014; Kim et al. 2011). Subsequently, combination of microRNA (miRNA) and small molecules are being investigated along with the key transcription factors to generate efficient and non-viral integrating neurons (Yoo et al. 2011; Jiang et al. 2015; Lau et al. 2014) (Fig. 1). In this review, we discuss the recent research progress of the direct conversion from fibroblasts to mDA neurons.
Fig. 1
Fig. 1

Schematic comparison between iPSC technology and direct conversion to generate DA neurons from skin fibroblasts in vitro for biomedical application. IPSC geneartion requires a forced expression/induction of reprogramming factors or small molecules. Several differentiation protocols provide robust yields of DA neurons highly resembling DA neuron characteristics with effective recovery of animal PD model. Direct induced dopamine neurons are derived from skin fibroblasts, which minimizes undesired differentiation potential and risks for teratoma formation

Key transcription factors during dopamine neuron development

Mash1 (also known as achaete-scute homolog 1, Ascl1)

Mash1 (mammalian achaete scute homolog-1) is a pro-neural transcription factor, which serves multiple roles in neuronal commitment. In brain development, neurogenesis is an essential process that drives neural progenitors into functional differentiated neurons. This neurogenesis is coordinated by pro-neural transcription factors including Mash1, Ngn1, and Ngn2. Especially, Mash1 is responsible for the neuronal cell specification, by binding with other neural pro-neural genes such as Ngn1 and Ngn2 (Parras et al. 2002; Cau et al. 2002). In sympathetic ganglia, Mash1 facilitates noradrenergic neuron differentiation by inducing expression of the homeobox gene Phox2a and the noradrenaline-synthesizing enzyme dopamine β-hydroxylase 1 (DBH1) (Lo et al. 1998; Hirsch et al. 1998). In the neuroepithelium of the hindbrain, Mash1 is indispensible for the differentiation of central serotonergic neurons (Pattyn et al. 2004). Genome-wide analysis of Mash1-mediated target genes in neural tube during murine embryogenesis revealed that Mash1 directly regulates numerous genes involved in proliferation, differentiation, and maturation of neurons by binding to the specific sequence, E-Box motif (CAGCTG) (Borromeo et al. 2014). Indeed, Mash1-deficient mice exhibit a severe loss of neural progenitors in the subventricular zone and abnormal ventral forebrain differentiation (Casarosa et al. 1999; Horton et al. 1999). Therefore, Mash1 is an important transcription factor, which promotes the neural lineage differentiation and context-dependent proliferation (Vasconcelos and Castro 2014).

Lmx1a and Foxa2

During early brain development, mDA neurons are derived from the ventral midline of the mesencephalon by the combined action of morphogen molecules and transcriptional factors. The initial event of mDA neuron development is regulated by sonic hedgehog (SHH) and wingless-related MMTV integration site 1 (Wnt1) (Arenas et al. 2015). The morphogen, SHH, directly induces the expression of Foxa2 in the ventral mesencephalon (VM) at embryonic day 8 (E8). Foxa2 regulates the extent of neurogenesis of mDA progenitors by inducing Ngn2 (Neurog 2) and sequentially differentiates immature mDA neurons by inducing Nurr1 (Sasaki et al. 1997; Ferri et al. 2007) (Fig. 2). Meanwhile, the glycoprotein Wnt1 secreted from midbrain-hindbrain border (MHB) directly induces the expression Lmx1 through the β-catenin complex. Lmx1 sequentially induces the expression of Nurr1 and Pitx3 for mDA neurons differentiation (Chung et al. 2009; Wurst and Prakash 2014) (Fig. 2). Therefore, transcriptional activity of Lmx1 and Foxa2 is required in floor-plate formation as well as mDA progenitor induction. Lmx1a is a protein that is involved in the proliferation, specification, and early differentiation of the mesodiencephalic DA progenitors into mDA neurons. In the murine brain development, Lmx1a is expressed by E.8.5 in the dorsal midline (roof plate) of the neural tube and in the optic vesicles (Failli et al. 2002). Thereafter, Lmx1a is highly expressed in the DA progenitors arising from the VM floor plate. During early neurogenesis of DA progenitors, Lmx1a induces Msx1 (Msh homeobox homolog 1) expression, which drives the expression of neurogenin 2 (Ngn2), a key transcription factor involved in neurogenesis and neural specification (Parras et al. 2002; Andersson et al. 2006; Roybon et al. 2008) (Fig. 2). Indeed, a severe reduction in the midbrain is observed in Lmx1a-deficient mice and dreher mutant mice, which are Lmx1a functional mutants (Mishima et al. 2009; Millonig et al. 2000). Therefore, Lmx1a is necessary for mDA neuron characterization. Foxa2 is a transcriptional factor that serves crucial role in mDA neuron specification during E7.5–E9.5. During mDA neuronal development, Foxa1 and Foxa2 are key regulatory factors, which regulate neurogenesis in the mDA progenitors by inducing the expression of Lmx1a and Ngn2 (Ferri et al. 2007; Lin et al. 2009). Lmx1a and Ngn2 cooperatively facilitate mDA neuronal differentiation. Moreover, Foxa1 and Foxa2-induced Nurr1 and engrailed 1 (en-1) increase the expression of aromatic l-amino acid decarboxylase (AADC) and tyrosine hydrolase (TH) in immature dopaminergic neurons (Ferri et al. 2007). The genetic ablation of Foxa1 and Foxa2 causes a severe loss of TH-positive mDA neurons (Stott et al. 2013). Moreover, a conditional deletion of Foxa1 and Foxa2 in adulthood also leads to the reduction of TH-positive adult dopaminergic neurons in ventral midbrain (Domanskyi et al. 2014). Therefore, the transcriptional activity of Foxa1 and Foxa2 is required in the mDA neuronal development.
Fig. 2
Fig. 2

Schematic interactions between transcription factors and morphogen molecules in the process of the specification, neurogenesis, and differentiation of mDA neurons. Two secreted morphogen molecules (SHH, Wnt1) control the patterning of dopaminergic progenitors through a reciprocal induction of Foxa2 and Lmx1a transcription factors. Subsequently, essential proneural gene, Ngn2, is induced by directly Foxa2 and indirectly Lmx1a (through Msx1) to promote the neurogenesis of dopaminergic precursor cells. Meanwhile, the sustained expression of Foxa2 and Lmx1a begins to induce the dopaminergic differentiation by increasing Nurr1 transcription. The evoked Nurr1 directly leads to the expression of various essential enzymes and transporters in dopaminergic differentiation. The abbreviated designations are the following: sonic hedgehog (SHH), wingless-related MMTV integration site 1 (Wnt1), Msh homeobox homolog (Msx1), neurogenin 2 (Ngn2), nuclear receptor-related factor 1 (Nurr1), dopamine transporter (DAT), tyrosine hydrolase (TH), and vesicular monoamine transporter 2 (VMAT2)

Nurr1 (also known as NR4A2)

Nurr1 is an orphan nuclear receptor that serves essential roles for the differentiation, maturation, and maintenance of mDA neurons. In the murine brain development, Nurr1 is expressed around E10.5 in the ventral midbrain prior to expression of TH, which is a key enzyme to generate dopamine at E11.5. Nurr1 expression is retained in DA neurons of the substantia nigra and ventral tegmental area (SN-VTA) throughout adulthood. Therefore, Nurr1 may be involved in the early stage of mDA neuronal differentiation as well as in the postnatal stage of mDA neuron maintenance. Moreover, SHH-Foxa2 and Wnt1-Lmx1 axis orchestrate the expression of Nurr1, suggesting that Nurr1 expression is a molecular cue for the development of mDA neurons.

Three conserved DNA-binding domains of Nurr1 are important for its transcriptional activity. NGFI-B response element (NBRE, AAAGGTCA) is crucial for Nurr1 function as a monomer, Nurr response element (NurRE, AAAT(G/A)(C/T)CA) is important for homodimers or heterodimers with NR4A family (Nur77 or Nor1), and direct repeat of AGGTCA with a five-base-pair spacer (DR5) is required for heterodimer with RXR (Campos-Melo et al. 2013). Importantly, Nurr1 induces the expression of TH as well as dopamine transporter (DAT) to maintain dopamine levels in synaptic cleft (Sakurada et al. 1999; Schimmel et al. 1999; Sacchetti et al. 2001). Subsequent studies have revealed that Nurr1 induces essential genes for the mDA neuronal function such as vesicular monoamine transporter 2 (VMAT2), aromatic amino acid carboxylase (AADC), and Ret (GDNF receptor) (Hermanson et al. 2003; Smits et al. 2003; Li et al. 2009).

Indeed, Nurr1-deficient mice are incapable of generating mDA neurons in the SN and VTA. However, these mice eventually died within the first 2 days of birth due to milk-suckling difficulty (Zetterstrom et al. 1997). A study using conditional Nurr1-gene targeted mice, in which Nurr1 is selectively ablated in mature DA neurons, showed progressive reduction in both developing and adult striatal DA neurons (Kadkhodaei et al. 2013). Moreover, selective Nurr1 deletion in mature DA neurons at adulthood (~ 5 weeks) results in typical pathological phenotypes seen in PD patients: (1) degeneration of DA neurons, (2) reduced dopamine and dopamine-related metabolites, and (3) impaired motor behaviors. Collectively, Nurr1 plays an indispensable role for generating and maintaining DA neurons by regulating numerous genes including dopamine-related enzymes, transporters, and transcription factors.

Generation of DA neurons from fibroblasts

Research on the generation of DA neurons from fibroblasts was inspired from the finding of direct conversion that generation of neurons using three transcription factors Ascl1, Brn2 and Myt1l (Vierbuchen et al. 2010). To determine which transcription factor is required for induced mDA neuron generation, Pfisterer and colleagues examined 10 genes involved in patterning and specification of DA neurons (En1, Foxa2, Gli1, Lmx1a, Lmx1b, Msx1, Nurr1, Otx1, Pax2, and Pax5). They found that Foxa2 and Lmx1a in combination with the three known genes (Ascl1, Brn2, and Myt1l) are required for induced DA neuron generation (Pfisterer et al. 2011). Consequently, Caiazzo and colleagues reported the minimal transcription factor combination (Ascl1, Nurr1, and Lmx1a) for generating induced DA neurons from mouse and human fibroblasts (Caiazzo et al. 2011). Induced DA neurons from murine fibroblasts alleviate symptoms in a mouse model of PD (Kim et al. 2011). Transcription factors including Axcl1, Nurr1, and Lmx1b induce direct conversion into DA neurons from astrocytes (Addis et al. 2011). Collectively, the ectopic expression of genes that are known to serve crucial function in the DA neuron specification and development is required for the generation of induced DA neurons.

MicroRNA-mediated conversion into dopamine neurons from fibroblasts

miRNA is an endogenous small non-coding molecule found in many organisms including plants, animals, and viruses (Dethoff et al. 2012). miRNA regulates gene expression by binding to complementary sequences (Vidigal and Ventura 2015). Numerous studies showed the close relationship between microRNA and neuronal development (Behm and Ohman 2016). Especially, miR-133b is expressed in the DA neurons and is deficient in PD patients. MiR-133b regulates function and maturation of DA neurons (Kim et al. 2007). Subsequent study showed that miR-9 and miR-124 repress BAF53a in post-mitotic neurons, regulating essential transition of neurogenesis (Yoo et al. 2011; Yoo et al. 2009). Interestingly, ectopic expression of miR-9 and miR-124 induces neuron-like morphological change in fibroblasts (Yoo et al. 2009). Combination of miR-124 and two transcriptional factors, Ascl1 and Myt1l, promote into human-induced neuron (ihN) generation from human primary dermal fibroblasts (Yoo et al. 2011). Collectively, these studies suggest that miRNAs involved in neuronal development could play an important role for generating neurons directly from fibroblasts. A more rigorous approach will be required to elucidate molecular mechanism of miRNA-mediated neuronal differentiation, specifically DA neuron differentiation.

Recent studies of induced DA neurons

The lentiviral vector system has been widely used to generate induced neurons from fibroblasts (Caiazzo et al. 2011; Pfisterer et al. 2011; Kim et al. 2014; Kim et al. 2011). Although this system is efficient to generate induced neurons, it is not safe for clinical use due to the possibility of transformation by lentiviral elements. Thus, alternative methods including non-integrating vector and chemical (small molecules) combinations have been investigated (Yoo et al. 2011; Jiang et al. 2015; Lau et al. 2014). The advantage of small molecules is the rapid, reversible, and dose-dependent effect, which allows control of the outcome by applying different concentration and combinations. Small molecules target key factors including transcription factors that regulate cell differentiation and reprogramming. Thus, small molecules have been widely used for generating iPSC and iPSC-derived DA neurons (Hou et al. 2013; Zhu et al. 2010; Li et al. 2011; Chen et al. 2011; Huangfu et al. 2008; Mali et al. 2010; Kriks et al. 2011; Studer 2012; Sundberg et al. 2013; Doi et al. 2014; Kirkeby et al. 2012; Ma et al. 2011). For example, epigenetic-related small molecules including HDAC inhibitors promote mouse embryonic fibroblasts reprogramming into iPSC (Huangfu et al. 2008; Mali et al. 2010). GSK3 inhibitors support embryonic stem cell (ESC) self-renewal and also facilitate rapid and efficient generation of iPSC (Li et al. 2009). Furthermore, there are small molecules that induce neural differentiation. SMAD inhibitors efficiently drive hESC to neural precursors through floor plate. SHH and FGF8 accelerates efficient generation of DA neuron precursors (Chambers et al. 2009). For ALK2, 3 and 6 inhibitors, LDN193189 facilitates neural conversion of human fibroblasts (Dai et al. 2015). Multiple studies have demonstrated direct conversion of DA neurons from fibroblasts using combination of small molecules and known transcription factors (summarized in Table 1).
Table 1

Summary of studies on induced mDA neuron differentiation from fibroblasts

Reference

Dopamine neuron differentiation

Transcription factor

miRNA

Chemical

Characteristics

Functional test

Pfisterer et al. 2011

Ascl1, Brn2, Myt1l, Foxa2, and Lmx1a

N/A

N/A

-16.43 ± 4.3% conversion efficiency to neuron

-Less than 10% of TH+ cells among neurons

-Electrophysiology

-Spontaneous action potentials and rebound action potentials are comparable with mDA neuron

Caiazzo et al. 2011

Ascl1, Nurr1, and Lmx1a

N/A

N/A

-ICC TH+ (~ 5%), VMAT2, DAT, ALDH1A1, and calbindin

-Gene expression pattern

-Electrophysiology

-Spontaneous action potentials and rebound action potentials are comparable with mDA neuron

-HPLC:DA release

Kim et al. 2011

Ascl1 and Pitx3

N/A

Shh + FGF in N3 media (N2 + bFGF)

-ICC TH+ (~ 5%), Tuj, DAT, and AADC

-Gene expression pattern

-Electrophysiology

-HPLC:DA release

-About 50% recovery in amphetamine-induced rotation

-About 2000 TH+ cells in grafted with elevated dopamine level

Addis et al. 2011

Ascl1, Lmx1b, and Nurr1

N/A

N/A

-ICC 35.15% of Tuj1+

50.9 ± 3.3% of TH+ among Tuj1+ cells (18.2 ± 1.5% conversion rate)

-Gene expression pattern

-Electrophysiology

-HPLC:DA release

Jiang et al. 2015

Ascl1, Lmx1a, Nurr1, and p53 shRNA

miR-124

Y27632/CHIR/VC/DM/SB/BDNF/PMN/NGF/GDNF/TGF-β

-ICC 93.3 ± 1.6% of Tuj1+, 59.2 ± 3.7% TH+

-Electrophysiology

-HPLC:DA release

iPSC-derived DA neuron vs. induced DA neuron

James Thompson and his colleagues established human embryonic stem cells (hESC) in 1998 (Thomson et al. 1998). hESC offers unlimited cell source not only for the inaccessible tissue but also for the development of diverse protocols including efficient generation of DA neurons. These efficient protocols are being used to generate iPSC-derived DA neurons, but there is a variation in differentiation potential of iPSCs (Hu et al. 2010). A subsequent study showed that treatment by a combination of small molecules efficiently induces hESC, iPSC, and PiPSC-derived DA neurons that (1) express dopamine neuronal markers in vitro, (2) exhibit robust TH positive neuritis innervation of the host striatum, and (3) show recovery in 6-OHDA PD rat model (Sundberg et al. 2013). This result indicated that iPSC-derived DA neurons could be a potent alternative cell source for PD. However, eliminating undifferentiated and undesired cell populations during iPSC-derived DA neuron generation is one of the major hurdles for clinical use of iPSC-derived DA neuron (Trounson and DeWitt 2016; Gutierrez-Aranda et al. 2010; Katsukawa et al. 2016; Lu and Zhao 2013). Especially, undifferentiated autologous iPSC can form teratoma, which does not fulfill clinical criteria. Induced neurons directly generated from fibroblasts that undergo senescence after several passages do not require cell proliferation, which is a necessary condition for iPSC reprogramming, eliminating the risk of teratoma. Although generation of DA neurons by direct conversion is faster compared to iPSC-derived DA neuron generation, there is a practical limitation to generate sufficient numbers of induced neurons by direct conversion for therapeutic use (Yang et al. 2011). Based on postmortem analysis from fetal VM transplantation in PD patients, large numbers of TH-positive cells (200,000~400,000) are required (Mendez et al. 2005; Li et al. 2008; Kordower et al. 1996; Hagell et al. 1999; Mendez et al. 2008). Therefore, it would be desirable to generate DA neuron precursors from fibroblasts that are expendable (Kim et al. 2014; Tian et al. 2015; Lim et al. 2015).

Conclusions

Despite the short amount of time since the report of direct conversion into neuronal cells from fibroblasts, it already represents a significant shift that cell fate plasticity can be manipulated by transcription factors (Vierbuchen et al. 2010; Pfisterer et al. 2011; Kim et al. 2011). Although the molecular mechanism is still poorly understood, this new methodology may be a strong and attractive tool to expand our knowledge on the relationship between transcription factors and various repressive/active chromatin states to regulate cell fate decision. Moreover, direct conversion of DA neurons provides an alternative for the cell-based therapy using iPSC technology. Recently, disease modeling using iPSC-derived neurons has provided new insights into the cellular aspect of diseases by recapitulating patient derived cells (Nishizawa et al. 2016; Mucci et al. 2016; Li et al. 2016; Heman-Ackah et al. 2016; Jang and Ye 2016; Choi et al. 2016; Mekhoubad et al. 2012; Marchetto et al. 2011; Soldner and Jaenisch 2012). Consequently, progerin-mediated late-onset disease modeling provides the possibility of using iPSC-derived DA neurons in late-onset age-related diseases (e.g., Parkinson’s diseases) (Miller et al. 2013). Along with the advance of iPSC-based disease modeling, induced mDA neurons from patient-derived fibroblasts will be beneficial for recapitulating diseases in vitro. Although small molecule-mediated generation of functional DA neuron from iPSC has been established, direct conversion of fibroblasts into DA neurons using only small molecules has not been established. This may be due to the different epigenetic control and chromatin statuses that are involved in cell fate plasticity, compared to those in iPSCs. Thus, more rigorous approaches are required to screen effective small molecules that regulate epigenetic changes in fibroblasts. Recent studies showed the close relationship between metabolites and epigenetic control in stem cell self-renewal and differentiation (Donohoe and Bultman 2012; Inagaki et al. 2016; Ryall et al. 2015; Berger and Sassone-Corsi 2015; Menendez 2015; Ryall et al. 2015; Ost and Pospisilik 2015; Meier 2013; Agathocleous and Harris 2013; Kaelin and McKnight 2013; Lu and Thompson 2012; Hanover et al. 2012). Acetyl-CoA, methionine, and α-ketoglutarate are the key metabolites that are either a source or cofactor of acetylation, methylation, and dimethylation. Moreover, metabolites like glucosamine-induced stem cell proliferation and differentiation by regulating both epigenetic control and anabolic metabolism (Hwang et al. 2016; TeSlaa et al. 2016; Carey et al. 2015; Jung et al. 2016; Jang et al. 2012). Thus, metabolic reprogramming is one of the candidates to further examine for regulation of cell fate plasticity. Future investigation will need to overcome the low efficiency of induced DA neurons from adult human fibroblasts.

Abbreviations

6-OHDA: 

6-Hydroxydopamine

AADC: 

Aromatic l-amino acid decarboxylase

ALK2: 

Activin A receptor type 2

BAF53a: 

BAF complex 53 KDa subunit

BDNF: 

Brain-derived neurotrophic factor

Brn2 also POU3F2: 

POU class 3 homeobox 2

CHIR: 

CHIR99021

DA neurons: 

Dopamine neurons

DAT: 

Dopamine transporter

DBH1: 

Noradrenaline-synthesizing enzyme dopamine β-hydroxylase 1

DM: 

Dorsomorphin

DR5: 

Five-base-pair spacer

en-1: 

Engrailed 1

FGF8: 

Fibroblast growth factor 8

Foxa2: 

Forkhead Box A2

GDNF: 

Glial cell line-derived neurotrophic factor

Gli1: 

Gli family zinc finger1

GSK3: 

Glycogen synthase kinase 3

HDAC: 

Histone deacetylase

ihN: 

Human-induced neuron

iPSC: 

Induced pluripotent stem cell

Lmx1a: 

LIM homeobox transcription factor 1 α

Mash1 also known as Ascl1: 

Mammalian achaete scute homolog-1

mDA neuron: 

Midbrain dopamine neuron

MHB: 

Midbrain-hindbrain border

miRNA: 

MicroRNA

Msx1: 

Msh homeobox homolog 1

MyoD: 

Myogenic differentiation 1

Myt1l: 

Myelin transcription factor 1 like

NGF: 

Nerve growth factor

Ngn1: 

Neurogenin 1

Ngn2: 

Neurogenin 2

Nurr1: 

Nuclear receptor-related 1 protein

Otx1: 

Orthodenticle homeobox1

Pax2: 

Paired box 2

Pax5: 

Paired box 5

PD: 

Parkinson’s disease

Phox2a: 

Paired like homeodomain 2a

PiPSC: 

Primate iPSC

PMN: 

Purmorphamine

RXR: 

Retinoic X receptor

SB: 

SB431542

SHH: 

Sonic hedgehog

SN: 

Substantia nigra

TH: 

Tyrosine hydrolase

VC: 

Vitamin C

VM: 

Ventral mesencephalon

VTA: 

Ventral tegmental area

Wnt1: 

Wingless-related MMTV integration site 1

Y27632: 

Rock inhibitor

Declarations

Acknowledgements

We thank Dr. Jeha Jeon for editing the figures. We are grateful to Dabin Hwang for the proofreading of the manuscript.

Funding

Not applicable.

Availability of data and materials

Not applicable.

Authors’ contributions

YJ and JHJ wrote the manuscript and figures. JHJ decided on the content, had editorial input on all sections, and designed the layout of figures. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Molecular Neurobiology Laboratory, McLean Hospital and Program in Neuroscience, Harvard Medical School, 115 Mill St. Mail stop 149, Belmont, MA 02478-1064, USA

References

  1. Addis RC, Hsu FC, Wright RL, Dichter MA, Coulter DA, Gearhart JD. Efficient conversion of astrocytes to functional midbrain dopaminergic neurons using a single polycistronic vector. PLoS One. 2011;6(12):e28719.PubMedPubMed CentralView ArticleGoogle Scholar
  2. Agathocleous M, Harris WA. Metabolism in physiological cell proliferation and differentiation. Trends Cell Biol. 2013;23(10):484–92.PubMedView ArticleGoogle Scholar
  3. Andersson E, Tryggvason U, Deng Q, Friling S, Alekseenko Z, Robert B, Perlmann T, Ericson J. Identification of intrinsic determinants of midbrain dopamine neurons. Cell. 2006;124(2):393–405.PubMedView ArticleGoogle Scholar
  4. Arenas E, Denham M, Villaescusa JC. How to make a midbrain dopaminergic neuron. Development. 2015;142(11):1918–36.PubMedView ArticleGoogle Scholar
  5. Barker RA, Drouin-Ouellet J, Parmar M. Cell-based therapies for Parkinson disease-past insights and future potential. Nat Rev Neurol. 2015;11(9):492–503.PubMedView ArticleGoogle Scholar
  6. Behm M, Ohman M. RNA editing: a contributor to neuronal dynamics in the mammalian brain. Trends Genet. 2016;32(3):165–75.PubMedView ArticleGoogle Scholar
  7. Berger SL, Sassone-Corsi P. Metabolic signaling to chromatin. Cold Spring Harb Perspect Biol. 2015;Google Scholar
  8. Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci. 2000;3(12):1301–6.PubMedView ArticleGoogle Scholar
  9. Borromeo MD, Meredith DM, Castro DS, Chang JC, Tung KC, Guillemot F, Johnson JE. A transcription factor network specifying inhibitory versus excitatory neurons in the dorsal spinal cord. Development. 2014;141(14):2803–12.PubMedPubMed CentralView ArticleGoogle Scholar
  10. Caiazzo M, Dell'Anno MT, Dvoretskova E, Lazarevic D, Taverna S, Leo D, Sotnikova TD, Menegon A, Roncaglia P, Colciago G, et al. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature. 2011;476(7359):224–7.PubMedView ArticleGoogle Scholar
  11. Campos-Melo D, Galleguillos D, Sanchez N, Gysling K, Andres ME. Nur transcription factors in stress and addiction. Front Mol Neurosci. 2013;6:44.PubMedPubMed CentralView ArticleGoogle Scholar
  12. Carey BW, Finley LW, Cross JR, Allis CD, Thompson CB. Intracellular alpha-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature. 2015;518(7539):413–6.PubMedView ArticleGoogle Scholar
  13. Casarosa S, Fode C, Guillemot F. Mash1 regulates neurogenesis in the ventral telencephalon. Development. 1999;126(3):525–34.PubMedGoogle Scholar
  14. Cau E, Casarosa S, Guillemot F. Mash1 and Ngn1 control distinct steps of determination and differentiation in the olfactory sensory neuron lineage. Development. 2002;129(8):1871–80.PubMedGoogle Scholar
  15. Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009;27(3):275–80.PubMedPubMed CentralView ArticleGoogle Scholar
  16. Chen G, Gulbranson DR, Hou Z, Bolin JM, Ruotti V, Probasco MD, Smuga-Otto K, Howden SE, Diol NR, Propson NE, et al. Chemically defined conditions for human iPSC derivation and culture. Nat Methods. 2011;8(5):424–9.PubMedPubMed CentralView ArticleGoogle Scholar
  17. Choi IY, Lim H, Estrellas K, Mula J, Cohen TV, Zhang Y, Donnelly CJ, Richard JP, Kim YJ, Kim H, et al. Concordant but varied phenotypes among Duchenne muscular dystrophy patient-specific myoblasts derived using a human iPSC-based model. Cell Rep. 2016;15(10):2301–12.PubMedView ArticleGoogle Scholar
  18. Chung S, Leung A, Han BS, Chang MY, Moon JI, Kim CH, Hong S, Pruszak J, Isacson O, Kim KS. Wnt1-lmx1a forms a novel autoregulatory loop and controls midbrain dopaminergic differentiation synergistically with the SHH-FoxA2 pathway. Cell Stem Cell. 2009;5(6):646–58.PubMedPubMed CentralView ArticleGoogle Scholar
  19. Dai P, Harada Y, Takamatsu T. Highly efficient direct conversion of human fibroblasts to neuronal cells by chemical compounds. J Clin Biochem Nutr. 2015;56(3):166–70.PubMedPubMed CentralView ArticleGoogle Scholar
  20. Davis RL, Weintraub H, Lassar AB. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell. 1987;51(6):987–1000.PubMedView ArticleGoogle Scholar
  21. de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006;5(6):525–35.PubMedView ArticleGoogle Scholar
  22. Dethoff EA, Chugh J, Mustoe AM, Al-Hashimi HM. Functional complexity and regulation through RNA dynamics. Nature. 2012;482(7385):322–30.PubMedPubMed CentralView ArticleGoogle Scholar
  23. Doi D, Samata B, Katsukawa M, Kikuchi T, Morizane A, Ono Y, Sekiguchi K, Nakagawa M, Parmar M, Takahashi J. Isolation of human induced pluripotent stem cell-derived dopaminergic progenitors by cell sorting for successful transplantation. Stem Cell Reports. 2014;2(3):337–50.PubMedPubMed CentralView ArticleGoogle Scholar
  24. Domanskyi A, Alter H, Vogt MA, Gass P, Vinnikov IA. Transcription factors Foxa1 and Foxa2 are required for adult dopamine neurons maintenance. Front Cell Neurosci. 2014;8:275.PubMedPubMed CentralView ArticleGoogle Scholar
  25. Donohoe DR, Bultman SJ. Metaboloepigenetics: interrelationships between energy metabolism and epigenetic control of gene expression. J Cell Physiol. 2012;227(9):3169–77.PubMedPubMed CentralView ArticleGoogle Scholar
  26. Failli V, Bachy I, Retaux S. Expression of the LIM-homeodomain gene Lmx1a (dreher) during development of the mouse nervous system. Mech Dev. 2002;118(1-2):225–8.PubMedView ArticleGoogle Scholar
  27. Ferri AL, Lin W, Mavromatakis YE, Wang JC, Sasaki H, Whitsett JA, Ang SL. Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner. Development. 2007;134(15):2761–9.PubMedView ArticleGoogle Scholar
  28. Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med. 2001;344(10):710–9.PubMedView ArticleGoogle Scholar
  29. Gutierrez-Aranda I, Ramos-Mejia V, Bueno C, Munoz-Lopez M, Real PJ, Macia A, Sanchez L, Ligero G, Garcia-Parez JL, Menendez P. Human induced pluripotent stem cells develop teratoma more efficiently and faster than human embryonic stem cells regardless the site of injection. Stem Cells. 2010;28(9):1568–70.PubMedPubMed CentralView ArticleGoogle Scholar
  30. Hagell P, Schrag A, Piccini P, Jahanshahi M, Brown R, Rehncrona S, Widner H, Brundin P, Rothwell JC, Odin P, et al. Sequential bilateral transplantation in Parkinson’s disease: effects of the second graft. Brain. 1999;122(Pt 6):1121–32.PubMedView ArticleGoogle Scholar
  31. Hanover JA, Krause MW, Love DC. Bittersweet memories: linking metabolism to epigenetics through O-GlcNAcylation. Nat Rev Mol Cell Biol. 2012;13(5):312–21.PubMedView ArticleGoogle Scholar
  32. Heins N, Malatesta P, Cecconi F, Nakafuku M, Tucker KL, Hack MA, Chapouton P, Barde YA, Gotz M. Glial cells generate neurons: the role of the transcription factor Pax6. Nat Neurosci. 2002;5(4):308–15.PubMedView ArticleGoogle Scholar
  33. Heman-Ackah SM, Bassett AR, Wood MJ. Precision modulation of neurodegenerative disease-related gene expression in human iPSC-derived neurons. Sci Rep. 2016;6:28420.PubMedPubMed CentralView ArticleGoogle Scholar
  34. Hermanson E, Joseph B, Castro D, Lindqvist E, Aarnisalo P, Wallen A, Benoit G, Hengerer B, Olson L, Perlmann T. Nurr1 regulates dopamine synthesis and storage in MN9D dopamine cells. Exp Cell Res. 2003;288(2):324–34.PubMedView ArticleGoogle Scholar
  35. Hirsch MR, Tiveron MC, Guillemot F, Brunet JF, Goridis C. Control of noradrenergic differentiation and Phox2a expression by MASH1 in the central and peripheral nervous system. Development. 1998;125(4):599–608.PubMedGoogle Scholar
  36. Horton S, Meredith A, Richardson JA, Johnson JE. Correct coordination of neuronal differentiation events in ventral forebrain requires the bHLH factor MASH1. Mol Cell Neurosci. 1999;14(4-5):355–69.PubMedView ArticleGoogle Scholar
  37. Hotta A, Yamanaka S. From genomics to gene therapy: induced pluripotent stem cells meet genome editing. Annu Rev Genet. 2015;49:47–70.PubMedView ArticleGoogle Scholar
  38. Hou P, Li Y, Zhang X, Liu C, Guan J, Li H, Zhao T, Ye J, Yang W, Liu K, et al. Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science. 2013;341(6146):651–4.PubMedView ArticleGoogle Scholar
  39. Hu BY, Weick JP, Yu J, Ma LX, Zhang XQ, Thomson JA, Zhang SC. Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc Natl Acad Sci U S A. 2010;107(9):4335–40.PubMedPubMed CentralView ArticleGoogle Scholar
  40. Huangfu D, Maehr R, Guo W, Eijkelenboom A, Snitow M, Chen AE, Melton DA. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol. 2008;26(7):795–7.PubMedView ArticleGoogle Scholar
  41. Hwang IY, Kwak S, Lee S, Kim H, Lee SE, Kim JH, Kim YA, Jeon YK, Chung DH, Jin X, et al. Psat1-dependent fluctuations in alpha-ketoglutarate affect the timing of ESC differentiation. Cell Metab. 2016;Google Scholar
  42. Inagaki T, Sakai J, Kajimura S. Transcriptional and epigenetic control of brown and beige adipose cell fate and function. Nat Rev Mol Cell Biol. 2016;17(8):480–95.PubMedPubMed CentralView ArticleGoogle Scholar
  43. Jang H, Kim TW, Yoon S, Choi SY, Kang TW, Kim SY, Kwon YW, Cho EJ, Youn HD. O-GlcNAc regulates pluripotency and reprogramming by directly acting on core components of the pluripotency network. Cell Stem Cell. 2012;11(1):62–74.PubMedView ArticleGoogle Scholar
  44. Jang YY, Ye Z. Gene correction in patient-specific iPSCs for therapy development and disease modeling. Hum Genet. 2016;135(9):1041–58.PubMedView ArticleGoogle Scholar
  45. Jiang H, Xu Z, Zhong P, Ren Y, Liang G, Schilling HA, Hu Z, Zhang Y, Wang X, Chen S, et al. Cell cycle and p53 gate the direct conversion of human fibroblasts to dopaminergic neurons. Nat Commun. 2015;6:10100.PubMedPubMed CentralView ArticleGoogle Scholar
  46. Jung JH, Iwabuchi K, Yang Z, Loeken MR. Embryonic stem cell proliferation stimulated by altered anabolic metabolism from glucose transporter 2-transported glucosamine. Sci Rep. 2016;6:28452.PubMedPubMed CentralView ArticleGoogle Scholar
  47. Kadkhodaei B, Alvarsson A, Schintu N, Ramskold D, Volakakis N, Joodmardi E, Yoshitake T, Kehr J, Decressac M, Bjorklund A, et al. Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons. Proc Natl Acad Sci U S A. 2013;110(6):2360–5.PubMedPubMed CentralView ArticleGoogle Scholar
  48. Kaelin WG Jr, McKnight SL. Influence of metabolism on epigenetics and disease. Cell. 2013;153(1):56–69.PubMedPubMed CentralView ArticleGoogle Scholar
  49. Karagiannis P, Eto K. Ten years of induced pluripotency: from basic mechanisms to therapeutic applications. Development. 2016;143(12):2039–43.PubMedView ArticleGoogle Scholar
  50. Katsukawa M, Nakajima Y, Fukumoto A, Doi D, Takahashi J. Fail-safe therapy by gamma-ray irradiation against tumor formation by human-induced pluripotent stem cell-derived neural progenitors. Stem Cells Dev. 2016;25(11):815–25.PubMedView ArticleGoogle Scholar
  51. Kim HS, Kim J, Jo Y, Jeon D, Cho YS. Direct lineage reprogramming of mouse fibroblasts to functional midbrain dopaminergic neuronal progenitors. Stem Cell Res. 2014;12(1):60–8.PubMedView ArticleGoogle Scholar
  52. Kim J, Inoue K, Ishii J, Vanti WB, Voronov SV, Murchison E, Hannon G, Abeliovich A. A microRNA feedback circuit in midbrain dopamine neurons. Science. 2007;317(5842):1220–4.PubMedPubMed CentralView ArticleGoogle Scholar
  53. Kim J, Su SC, Wang H, Cheng AW, Cassady JP, Lodato MA, Lengner CJ, Chung CY, Dawlaty MM, Tsai LH, et al. Functional integration of dopaminergic neurons directly converted from mouse fibroblasts. Cell Stem Cell. 2011;9(5):413–9.PubMedPubMed CentralView ArticleGoogle Scholar
  54. Kirkeby A, Grealish S, Wolf DA, Nelander J, Wood J, Lundblad M, Lindvall O, Parmar M. Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions. Cell Rep. 2012;1(6):703–14.PubMedView ArticleGoogle Scholar
  55. Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med. 2008;14(5):504–6.PubMedView ArticleGoogle Scholar
  56. Kordower JH, Freeman TB, Chen EY, Mufson EJ, Sanberg PR, Hauser RA, Snow B, Olanow CW. Fetal nigral grafts survive and mediate clinical benefit in a patient with Parkinson’s disease. Mov Disord. 1998;13(3):383–93.PubMedView ArticleGoogle Scholar
  57. Kordower JH, Rosenstein JM, Collier TJ, Burke MA, Chen EY, Li JM, Martel L, Levey AE, Mufson EJ, Freeman TB, et al. Functional fetal nigral grafts in a patient with Parkinson’s disease: chemoanatomic, ultrastructural, and metabolic studies. J Comp Neurol. 1996;370(2):203–30.PubMedView ArticleGoogle Scholar
  58. Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, Carrillo-Reid L, Auyeung G, Antonacci C, Buch A, et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature. 2011;480(7378):547–51.PubMedPubMed CentralGoogle Scholar
  59. Kulessa H, Frampton J, Graf T. GATA-1 reprograms avian myelomonocytic cell lines into eosinophils, thromboblasts, and erythroblasts. Genes Dev. 1995;9(10):1250–62.PubMedView ArticleGoogle Scholar
  60. Lau S, Rylander Ottosson D, Jakobsson J, Parmar M. Direct neural conversion from human fibroblasts using self-regulating and nonintegrating viral vectors. Cell Rep. 2014;9(5):1673–80.PubMedView ArticleGoogle Scholar
  61. Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Bjorklund A, et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med. 2008;14(5):501–3.PubMedView ArticleGoogle Scholar
  62. Li L, Su Y, Zhao C, Xu Q. Role of Nurr1 and Ret in inducing rat embryonic neural precursors to dopaminergic neurons. Neurol Res. 2009;31(5):534–40.PubMedView ArticleGoogle Scholar
  63. Li M, Izpisua Belmonte JC. Looking to the future following 10 years of induced pluripotent stem cell technologies. Nat Protoc. 2016;11(9):1579–85.PubMedView ArticleGoogle Scholar
  64. Li M, Zhao H, Ananiev GE, Musser MT, Ness KH, Maglaque DL, Saha K, Bhattacharyya A, Zhao X. Establishment of reporter lines for detecting fragile X mental retardation (FMR1) gene reactivation in human neural cells. Stem Cells. 2016;Google Scholar
  65. Li W, Wei W, Zhu S, Zhu J, Shi Y, Lin T, Hao E, Hayek A, Deng H, Ding S. Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors. Cell Stem Cell. 2009;4(1):16–9.PubMedView ArticleGoogle Scholar
  66. Li Y, Zhang Q, Yin X, Yang W, Du Y, Hou P, Ge J, Liu C, Zhang W, Zhang X, et al. Generation of iPSCs from mouse fibroblasts with a single gene, Oct4, and small molecules. Cell Res. 2011;21(1):196–204.PubMedView ArticleGoogle Scholar
  67. Lim MS, Chang MY, Kim SM, Yi SH, Suh-Kim H, Jung SJ, Kim MJ, Kim JH, Lee YS, Lee SY, et al. Generation of dopamine neurons from rodent fibroblasts through the expandable neural precursor cell stage. J Biol Chem. 2015;290(28):17401–14.PubMedPubMed CentralView ArticleGoogle Scholar
  68. Lin W, Metzakopian E, Mavromatakis YE, Gao N, Balaskas N, Sasaki H, Briscoe J, Whitsett JA, Goulding M, Kaestner KH, et al. Foxa1 and Foxa2 function both upstream of and cooperatively with Lmx1a and Lmx1b in a feedforward loop promoting mesodiencephalic dopaminergic neuron development. Dev Biol. 2009;333(2):386–96.PubMedView ArticleGoogle Scholar
  69. Lo L, Tiveron MC, Anderson DJ. MASH1 activates expression of the paired homeodomain transcription factor Phox2a, and couples pan-neuronal and subtype-specific components of autonomic neuronal identity. Development. 1998;125(4):609–20.PubMedGoogle Scholar
  70. Lu C, Thompson CB. Metabolic regulation of epigenetics. Cell Metab. 2012;16(1):9–17.PubMedPubMed CentralView ArticleGoogle Scholar
  71. Lu X, Zhao T. Clinical therapy using iPSCs: hopes and challenges. Genomics Proteomics Bioinformatics. 2013;11(5):294–8.PubMedPubMed CentralView ArticleGoogle Scholar
  72. Ma L, Liu Y, Zhang SC. Directed differentiation of dopamine neurons from human pluripotent stem cells. Methods Mol Biol. 2011;767:411–8.PubMedView ArticleGoogle Scholar
  73. Mali P, Chou BK, Yen J, Ye Z, Zou J, Dowey S, Brodsky RA, Ohm JE, Yu W, Baylin SB, et al. Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigenetic remodeling and the expression of pluripotency-associated genes. Stem Cells. 2010;28(4):713–20.PubMedPubMed CentralView ArticleGoogle Scholar
  74. Marchetto MC, Brennand KJ, Boyer LF, Gage FH. Induced pluripotent stem cells (iPSCs) and neurological disease modeling: progress and promises. Hum Mol Genet. 2011;20(R2):R109–15.PubMedPubMed CentralView ArticleGoogle Scholar
  75. Meier JL. Metabolic mechanisms of epigenetic regulation. ACS Chem Biol. 2013;8(12):2607–21.PubMedPubMed CentralView ArticleGoogle Scholar
  76. Mekhoubad S, Bock C, de Boer AS, Kiskinis E, Meissner A, Eggan K. Erosion of dosage compensation impacts human iPSC disease modeling. Cell Stem Cell. 2012;10(5):595–609.PubMedPubMed CentralView ArticleGoogle Scholar
  77. Mendez I, Sanchez-Pernaute R, Cooper O, Vinuela A, Ferrari D, Bjorklund L, Dagher A, Isacson O. Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson’s disease. Brain. 2005;128(Pt 7):1498–510.PubMedPubMed CentralView ArticleGoogle Scholar
  78. Mendez I, Vinuela A, Astradsson A, Mukhida K, Hallett P, Robertson H, Tierney T, Holness R, Dagher A, Trojanowski JQ, et al. Dopamine neurons implanted into people with Parkinson’s disease survive without pathology for 14 years. Nat Med. 2008;14(5):507–9.PubMedPubMed CentralView ArticleGoogle Scholar
  79. Menendez JA. Metabolic control of cancer cell stemness: lessons from iPS cells. Cell Cycle. 2015;14(24):3801–11.PubMedPubMed CentralView ArticleGoogle Scholar
  80. Mertens J, Marchetto MC, Bardy C, Gage FH. Evaluating cell reprogramming, differentiation and conversion technologies in neuroscience. Nat Rev Neurosci. 2016;17(7):424–37.PubMedView ArticleGoogle Scholar
  81. Miller JD, Ganat YM, Kishinevsky S, Bowman RL, Liu B, Tu EY, Mandal PK, Vera E, Shim JW, Kriks S, et al. Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell. 2013;13(6):691–705.PubMedPubMed CentralView ArticleGoogle Scholar
  82. Millonig JH, Millen KJ, Hatten ME. The mouse dreher gene Lmx1a controls formation of the roof plate in the vertebrate CNS. Nature. 2000;403(6771):764–9.PubMedView ArticleGoogle Scholar
  83. Mishima Y, Lindgren AG, Chizhikov VV, Johnson RL, Millen KJ. Overlapping function of Lmx1a and Lmx1b in anterior hindbrain roof plate formation and cerebellar growth. J Neurosci. 2009;29(36):11377–84.PubMedView ArticleGoogle Scholar
  84. Mucci A, Kunkiel J, Suzuki T, Brennig S, Glage S, Kuhnel MP, Ackermann M, Happle C, Kuhn A, Schambach A, et al. Murine iPSC-derived macrophages as a tool for disease modeling of hereditary pulmonary alveolar proteinosis due to Csf2rb deficiency. Stem Cell Reports. 2016;7(2):292–305.PubMedPubMed CentralView ArticleGoogle Scholar
  85. Nishizawa M, Chonabayashi K, Nomura M, Tanaka A, Nakamura M, Inagaki A, Nishikawa M, Takei I, Oishi A, Tanabe K, et al. Epigenetic variation between human induced pluripotent stem cell lines is an indicator of differentiation capacity. Cell Stem Cell. 2016;Google Scholar
  86. Olanow CW, Goetz CG, Kordower JH, Stoessl AJ, Sossi V, Brin MF, Shannon KM, Nauert GM, Perl DP, Godbold J, et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol. 2003;54(3):403–14.PubMedView ArticleGoogle Scholar
  87. Olanow CW, Kordower JH, Freeman TB. Fetal nigral transplantation as a therapy for Parkinson’s disease. Trends Neurosci. 1996;19(3):102–9.PubMedView ArticleGoogle Scholar
  88. Ost A, Pospisilik JA. Epigenetic modulation of metabolic decisions. Curr Opin Cell Biol. 2015;33:88–94.PubMedView ArticleGoogle Scholar
  89. Parras CM, Schuurmans C, Scardigli R, Kim J, Anderson DJ, Guillemot F. Divergent functions of the proneural genes Mash1 and Ngn2 in the specification of neuronal subtype identity. Genes Dev. 2002;16(3):324–38.PubMedPubMed CentralView ArticleGoogle Scholar
  90. Pattyn A, Simplicio N, van Doorninck JH, Goridis C, Guillemot F, Brunet JF. Ascl1/Mash1 is required for the development of central serotonergic neurons. Nat Neurosci. 2004;7(6):589–95.PubMedView ArticleGoogle Scholar
  91. Pfisterer U, Kirkeby A, Torper O, Wood J, Nelander J, Dufour A, Bjorklund A, Lindvall O, Jakobsson J, Parmar M. Direct conversion of human fibroblasts to dopaminergic neurons. Proc Natl Acad Sci U S A. 2011;108(25):10343–8.PubMedPubMed CentralView ArticleGoogle Scholar
  92. Roybon L, Hjalt T, Christophersen NS, Li JY, Brundin P. Effects on differentiation of embryonic ventral midbrain progenitors by Lmx1a, Msx1, Ngn2, and Pitx3. J Neurosci. 2008;28(14):3644–56.PubMedView ArticleGoogle Scholar
  93. Ryall JG, Cliff T, Dalton S, Sartorelli V. Metabolic reprogramming of stem cell epigenetics. Cell Stem Cell. 2015;17(6):651–62.PubMedPubMed CentralView ArticleGoogle Scholar
  94. Ryall JG, Dell'Orso S, Derfoul A, Juan A, Zare H, Feng X, Clermont D, Koulnis M, Gutierrez-Cruz G, Fulco M, et al. The NAD(+)-dependent SIRT1 deacetylase translates a metabolic switch into regulatory epigenetics in skeletal muscle stem cells. Cell Stem Cell. 2015;16(2):171–83.PubMedPubMed CentralView ArticleGoogle Scholar
  95. Sacchetti P, Mitchell TR, Granneman JG, Bannon MJ. Nurr1 enhances transcription of the human dopamine transporter gene through a novel mechanism. J Neurochem. 2001;76(5):1565–72.PubMedView ArticleGoogle Scholar
  96. Sakurada K, Ohshima-Sakurada M, Palmer TD, Gage FH. Nurr1, an orphan nuclear receptor, is a transcriptional activator of endogenous tyrosine hydroxylase in neural progenitor cells derived from the adult brain. Development. 1999;126(18):4017–26.PubMedGoogle Scholar
  97. Sasaki H, Hui C, Nakafuku M, Kondoh H. A binding site for Gli proteins is essential for HNF-3beta floor plate enhancer activity in transgenics and can respond to Shh in vitro. Development. 1997;124(7):1313–22.PubMedGoogle Scholar
  98. Schimmel JJ, Crews L, Roffler-Tarlov S, Chikaraishi DM. 4.5 kb of the rat tyrosine hydroxylase 5′ flanking sequence directs tissue specific expression during development and contains consensus sites for multiple transcription factors. Brain Res Mol Brain Res. 1999;74(1-2):1–14.PubMedView ArticleGoogle Scholar
  99. Shen CN, Slack JM, Tosh D. Molecular basis of transdifferentiation of pancreas to liver. Nat Cell Biol. 2000;2(12):879–87.PubMedView ArticleGoogle Scholar
  100. Smits SM, Ponnio T, Conneely OM, Burbach JP, Smidt MP. Involvement of Nurr1 in specifying the neurotransmitter identity of ventral midbrain dopaminergic neurons. Eur J Neurosci. 2003;18(7):1731–8.PubMedView ArticleGoogle Scholar
  101. Soldner F, Jaenisch R. Medicine. iPSC disease modeling. Science. 2012;338(6111):1155–6.PubMedView ArticleGoogle Scholar
  102. Stott SR, Metzakopian E, Lin W, Kaestner KH, Hen R, Ang SL. Foxa1 and foxa2 are required for the maintenance of dopaminergic properties in ventral midbrain neurons at late embryonic stages. J Neurosci. 2013;33(18):8022–34.PubMedView ArticleGoogle Scholar
  103. Studer L. Derivation of dopaminergic neurons from pluripotent stem cells. Prog Brain Res. 2012;200:243–63.PubMedView ArticleGoogle Scholar
  104. Sundberg M, Bogetofte H, Lawson T, Jansson J, Smith G, Astradsson A, Moore M, Osborn T, Cooper O, Spealman R, et al. Improved cell therapy protocols for Parkinson’s disease based on differentiation efficiency and safety of hESC-, hiPSC-, and non-human primate iPSC-derived dopaminergic neurons. Stem Cells. 2013;31(8):1548–62.PubMedView ArticleGoogle Scholar
  105. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.PubMedView ArticleGoogle Scholar
  106. Takahashi K, Yamanaka S. A decade of transcription factor-mediated reprogramming to pluripotency. Nat Rev Mol Cell Biol. 2016;17(3):183–93.PubMedView ArticleGoogle Scholar
  107. Tapia N, Scholer HR. Molecular obstacles to clinical translation of iPSCs. Cell Stem Cell. 2016;Google Scholar
  108. TeSlaa T, Chaikovsky AC, Lipchina I, Escobar SL, Hochedlinger K, Huang J, Graeber TG, Braas D, Teitell MA. Alpha-ketoglutarate accelerates the initial differentiation of primed human pluripotent stem cells. Cell Metab. 2016;Google Scholar
  109. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145–7.PubMedView ArticleGoogle Scholar
  110. Tian C, Li Y, Huang Y, Wang Y, Chen D, Liu J, Deng X, Sun L, Anderson K, Qi X, et al. Selective generation of dopaminergic precursors from mouse fibroblasts by direct lineage conversion. Sci Rep. 2015;5:12622.PubMedPubMed CentralView ArticleGoogle Scholar
  111. Trounson A, DeWitt ND. Pluripotent stem cells progressing to the clinic. Nat Rev Mol Cell Biol. 2016;17(3):194–200.PubMedView ArticleGoogle Scholar
  112. Vasconcelos FF, Castro DS. Transcriptional control of vertebrate neurogenesis by the proneural factor Ascl1. Front Cell Neurosci. 2014;8:412.PubMedPubMed CentralView ArticleGoogle Scholar
  113. Vidigal JA, Ventura A. The biological functions of miRNAs: lessons from in vivo studies. Trends Cell Biol. 2015;25(3):137–47.PubMedView ArticleGoogle Scholar
  114. Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Sudhof TC, Wernig M. Direct conversion of fibroblasts to functional neurons by defined factors. Nature. 2010;463(7284):1035–41.PubMedPubMed CentralView ArticleGoogle Scholar
  115. Wurst W, Prakash N. Wnt1-regulated genetic networks in midbrain dopaminergic neuron development. J Mol Cell Biol. 2014;6(1):34–41.PubMedView ArticleGoogle Scholar
  116. Xie H, Ye M, Feng R, Graf T. Stepwise reprogramming of B cells into macrophages. Cell. 2004;117(5):663–76.PubMedView ArticleGoogle Scholar
  117. Yang N, Ng YH, Pang ZP, Sudhof TC, Wernig M. Induced neuronal cells: how to make and define a neuron. Cell Stem Cell. 2011;9(6):517–25.PubMedPubMed CentralView ArticleGoogle Scholar
  118. Yoo AS, Staahl BT, Chen L, Crabtree GR. MicroRNA-mediated switching of chromatin-remodelling complexes in neural development. Nature. 2009;460(7255):642–6.PubMedPubMed CentralGoogle Scholar
  119. Yoo AS, Sun AX, Li L, Shcheglovitov A, Portmann T, Li Y, Lee-Messer C, Dolmetsch RE, Tsien RW, Crabtree GR. MicroRNA-mediated conversion of human fibroblasts to neurons. Nature. 2011;476(7359):228–31.PubMedPubMed CentralView ArticleGoogle Scholar
  120. Zetterstrom RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T. Dopamine neuron agenesis in Nurr1-deficient mice. Science. 1997;276(5310):248–50.PubMedView ArticleGoogle Scholar
  121. Zhu S, Li W, Zhou H, Wei W, Ambasudhan R, Lin T, Kim J, Zhang K, Ding S. Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell. 2010;7(6):651–5.PubMedView ArticleGoogle Scholar

Copyright

© The Author(s) 2017

Advertisement

Biomedical Dermatology

ISSN: 2398-8460

Contact us