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Published in final edited form as:
Science. 2013 December 20; 342(6165 Suppl): 50–52.
Neural Progenitors by Direct Reprogramming: Strategies for the
Treatment of Parkinson's and Alzheimer's Diseases
Changhai Tian1,2 and Jialin C. Zheng1,2,3,*
1Center
for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth
People's Hospital affiliated to Tongji University School of Medicine, Shanghai, China
2Department
of Pharmacology & Experimental Neuroscience, University of Nebraska Medical
Center, Omaha, Nebraska
3Department
of Pathology and Microbiology, University of Nebraska Medical Center, Omaha,
Nebraska
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Age-related neurodegenerative diseases, such as Parkinson's (PD) and Alzheimer′s (AD)
disease, are seriously threatening the health of Chinese citizens, with PD and AD patient
populations increasing at a rate of 100,000 and 300,000 per year, respectively (1, 2).
Although there is no cure for AD or PD, a variety of medications can provide relief from
some of the symptoms. Recently, the development of direct reprogramming technologies has
shed light on promising strategies for stem cell-based therapies for AD and PD. This review
will focus on neural progenitor cells and induced neural progenitor cells studied in our
laboratory, and discuss their potential applications in AD and PD treatment.
Neural Progenitors from Fetal Tissues
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Multipotent neural progenitor cells (NPCs) exist in the mammalian developing and adult
nervous system, and are capable of migrating toward the specific sites and giving rise to the
main components of the nervous system. Transplantation of NPCs is a promising therapy for
various neurodegenerative diseases and brain injuries (3–5). It has been reported that the
transplantation of NPCs into the brain contributes to the improvement of cognitive
impairment in animal models of PD and AD. This occurs through cell replacement, the
release of specific neurotransmitters, and the production of neurotrophic factors that protect
injured neurons and promote neuronal growth (6–10). The transplantation of NPCs derived
from fetal brain raises serious ethical concerns, particularly in the acquisition of the fetal
tissue, but the understanding gained from these in vitro experiments will be useful for the
future application of NPCs obtained from non-fetal sources. Our laboratory has been
working on human NPCs for many years and has revealed that C-X-C motif chemokine 12
(CXCL12, also known as stromal cell-derived factor 1) plays an important role not only in
increasing cell proliferation through the Akt/Foxo3a signaling pathway, but also in
protecting against NPC apoptosis through chemokine receptor CXCR7- and CXCR4mediated endocytotic signaling pathways (11, 12). These data provide insight into the
*
Corresponding Author: [email protected].
Tian and Zheng
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essential role for CXCL12 in neurogenesis and also suggests a novel role for CXCR7 in
NPC survival contributing to neurogenesis, as well as potentially offering some theoretical
guidance for NPC-based therapy.
Neural Progenitor Cells Generated by Direct Reprogramming
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Selective degeneration of functional neurons is associated with the pathogenesis of
neurodegenerative disorders, such as degeneration of midbrain dopaminergic neurons in PD
(13) and forebrain cholinergic neurons in AD (14). How to achieve sufficient cell
replacement to halt PD or AD progression, or possibly even provide a cure, is the main
challenge. The discovery of induced pluripotent stem (iPS) cells has facilitated the
derivation of stem cells from adult somatic cells for the personalized treatment of PD and
AD without depending on fetal tissues. However, ethical and safety concerns still exist.
Recently, neuronal subtypes including dopaminergic and cholinergic neurons have been
generated successfully through direct reprogramming of somatic cells by expression of
developmental genes (15–17). The low yield of neurons from this method has, however,
limited its broad application in cell transplantation. In addition to NPCs obtained from iPS
cell differentiation (Figure 1, path A) and neuronal subtypes induced by direct
reprogramming (Figure 1, path E), the direct reprogramming of NPCs from differentiated,
non-neuronal somatic cells (Figure 1, paths B and C) (18–21) will not only provide an
alternative to fetal tissue or pluripotent cells as precursors, but also furnish a potentially
unlimited source of neurons. Our laboratory was among the first to successfully convert
fibroblasts into induced NPCs (iNPCs) by ectopic expression of transcription factors. iNPCs
share many characteristics with primary NPCs and are able to differentiate into neurons
(Figure 2). Recently, the direct reprogramming of iNPCs has also been achieved by forced
expression of single factor (22) or by 3D sphere culture of fibroblasts on low attachment
surfaces (23). These findings suggest that neural progenitor cell fate can be reprogrammed
by modifying intrinsic and extrinsic cues.
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Stem cell-based therapy for AD and PD is essentially based on the regeneration of different
neuronal subtypes, such as dopaminergic neurons in PD and forebrain cholinergic neurons in
AD. Recently, we have been working on the direct reprogramming of somatic cells into
region-specific iNPCs (Figure 1, path D) as well as subtype-specific iNPCs (Figure 1, path
F) by overexpression of defined growth factors. Both of these pathways show promise for
AD and PD therapies. Direct in vivo conversion of somatic cells, such as fibroblasts and
astrocytes, into functional neurons has also been achieved (24), providing proof of principle
that it may be feasible to convert somatic cells—such as activated astrocytes—into regionor subtype-specific iNPCs in the brains of AD and PD patients. In the future, the further
development of this technology will undoubtedly provide promising strategies for the
effective treatment of AD and PD.
Acknowledgments
This work was supported in part by research grants from the National Institutes of Health (R01 NS 41858-01 and
R01 NS 061642-01), the State of Nebraska (DHHS-LB606 Stem Cell 2009-10 to J.Z. and LB606 Stem Cell
2010-10 to S.D. and C.T.), the China National Science and Technology major project (2014CB965001), and the
National Natural Science Foundation of China (81028007 and 81329002 to J.Z., and 81271419 to C.T.).
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Tian and Zheng
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Figure 1. Strategies to Generate iNPCs from Somatic Cells
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iNPCs can be induced by conceptually different mechanisms. (A) Ectopic expression of
Yamanaka factors converts somatic cells to induced pluripotent (iPS) cells that can then be
differentiated into primitive iNPCs, and subsequently into different subtypes of neurons
based on differentiation conditions. (B) Ectopic expression of Yamanaka factors converts
somatic cells to primitive iNPCs through an intermediate unstable pluripotent stage. (C)
Direct reprogramming of primitive iNPCs by expression of lineage-specific transcription
factors. (D) Direct reprogramming of region-specific iNPCs by expression of lineagespecific transcription factors and location-specific determinants. (E) Generation of neuronal
subtypes through direct conversion of cells in vitro and in vivo. (F) Generation of neuronal
progenitor subtypes of through direct conversion of somatic cells using sets of defined
transcription factor.
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Figure 2. Direct Conversion of Fibroblasts into NPCs by a Novel Combination of Transcription
Factors
(A) Schematic showing direct reprogramming of fibroblasts derived from E/Nestin:EGFP
transgenic mice into NPCs using defined transcription factors including Brn2, Sox2, Bmi1,
TLX and c-Myc. (B) Differentiation of iNPCs into neurons (panel a; MAP-2, red),
astrocytes (panel b; GFAP, red), oligodendrocytes (panel c; O4, red). Panel d shows synapse
formation between neurons (β-III Tubulin, green; Synaptophysin, red), with magnification
of white box in d shown in panel e. Nuclei are stained with DAPI (blue). EGFP, enhanced
green fluorescent protein; MAP-2, microtubule-associated protein 2; GFAP, glial fibrillary
acidic protein; O4, marker for oligodendrocytes.
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