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Chemical reprogramming of human glial cells into neurons for brain and spinal cord repair

A glial cell, glial cell technology, applied in the field of chemical reprogramming of human glial cells into nerve cells for brain and spinal cord repair, can address unmet, complex risks, potential immune injection, tumor Occurrence and differentiation uncertainty

Active Publication Date: 2017-09-26
PENN STATE RES FOUND
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Despite its great potential, this method of cell transplantation faces significant hurdles in clinical application, such as potential immunization injections, tumorigenesis, and differentiation uncertainty (Lee et al., 2013; Liu et al., 2013b; Lukovic et al., 2014)
Furthermore, although previous studies have shown that astrocytes can be expressed in vitro (Guo et al., 2014; ) directly into functional neurons, and astrocytes can convert into neuroblasts and subsequently differentiate into neural metacellular, these methods have the significant disadvantage of requiring viral infection in the brain
Thus, these previous methods required the performance of complex brain surgery, intracranial injection of viral particles, and considerable risk associated with these steps
Accordingly, there remains an ongoing and uninterrupted search for new compositions and methods for regenerating functional neurons in the central or peripheral nervous system without the need to introduce exogenously reprogrammed cells or viral constructs into human subjects. Satisfied needs

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  • Chemical reprogramming of human glial cells into neurons for brain and spinal cord repair
  • Chemical reprogramming of human glial cells into neurons for brain and spinal cord repair
  • Chemical reprogramming of human glial cells into neurons for brain and spinal cord repair

Examples

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Embodiment 1

[0066] This example demonstrates the successful reprogramming of human astrocytes into neurons by small molecules as described above. These experiments are designed to develop convenient methods for reprogramming human astrocytes into neurons using small molecules such as, but not limited to, oral administration drugs that can be easily taken by patients. Therefore, we investigated whether small molecules can replace neural transcription factors to reprogram glial cells into neurons. We use human cortical astrocytes (HA1800, ScienCell, San Diego, CA, USA) in culture for chemical reprogramming for clinical applications in human brain repair. Based on two main selection criteria: one ct inhibits glial signaling pathways and the other activates neuronal signaling pathways. We selected 20 small molecules as our starting candidate library. Some molecules are included because they can modulate DNA or histone structure to improve reprogramming efficiency. The 20 small molecules sele...

Embodiment 2

[0071] This example demonstrates that the small molecule transformed human neurons produced according to the present disclosure are fully functional in stimulating action potentials and releasing neurotransmitters. In particular, we found that neurons transformed by small molecules survived for a long time (> 5 months), and showed strong synapses along the dendrites ( figure 2 A). Similarly, neurons reprogrammed from midbrain human astrocytes and Gibco human astrocytes also survived more than 2 months in culture, with many synapses along the dendrites ( Picture 10 F, I). Patch-clamp recordings showed obvious sodium and potassium currents in neurons transformed by astrocytes, which gradually increased during the maturation of neurons ( figure 2 B-E; 2 months: I Na =1889±197Pa, n=10; I K =2722±263Pa, n=10). These neurons can trigger repetitive action potentials ( figure 2 F). More importantly, neurons transformed by small molecules showed strong spontaneous synaptic activit...

Embodiment 3

[0073] This example demonstrates that the small molecules described herein reprogram human astrocytes into forebrain glutamatergic neurons. In order to characterize the neuronal characteristics after reprogramming induced by small molecules, we examined neuronal markers expressed in the nervous system from the front to the back. We found that most of the neurons transformed by astrocytes were immunopositive for the forebrain marker FoxG1 (97.1±1.1%, image 3 A, n=3 batches), but it was negative for the hindbrain and spinal cord markers HoxB4 and HoxC9 ( image 3 B-C, n=3 batches). We next performed a series of immunostaining with various cortical neuron markers. We found that most of the neurons transformed by human astrocytes were immunonegative to the cortical surface marker Cux1 ( image 3 D), but for the deep marker Ctip2( image 3 E, 71.4±3%, n=5 batches) and Otx1( image 3 F) It is immunopositive. Transformed neurons from human astrocytes are paired with forebrain neuron...

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Abstract

Provided are methods and compositions from reprogramming human glial cells into human neurons. The reprogramming is achieved using combinations of compounds that can modify signaling via Transforming growth factor beta (TGF-beta), Bone morphogenetic protein (BMP), glycogen synthase kinase 3 (GSK-3), and gamma-secretase / Notch pathways. The reprogramming is demonstrated using groups of three or four compounds that are chosen from the group thiazovivin, LDN193189, SB431542, TTNPB, CHIR99021, DAPT, VPA, SAG, purmorphamine. Reprogramming is demonstrated using the group of LDN193189 / CHIR99021 / DAPT, the group of B431542 / CHIR99021 / DAPT, the group of LDN193189 / DAPT / SB431542, the group of LDN 193189 / CHIR99021 / SB431542, a three drug combination of SB431542 / CHIR99021 / DAPT. Reprogramming using functional analogs of the compounds is also provided, as are pharmaceutical formulations that contain the drug combinations.

Description

[0001] Cross references to related applications [0002] This application claims priority for the U.S. Provisional Application No. 62 / 084,365 filed on November 25, 2014 and the U.S. Provisional Application No. 62 / 215828 filed on September 9, 2015, and their respective disclosures are approved by The reference is incorporated into this article. [0003] Statement on Federal Government Funding of Research [0004] The present invention was completed with government support under the contract numbered MH083911 and AG045656 awarded by the National Institutes of Health. The government has certain rights in this invention. Technical field [0005] The present disclosure generally relates to the prevention and treatment of disorders related to glial scar tissue, and more specifically to a combination comprising small molecules used to convert internal glial cells into functional neurons for brain and spinal cord repair 物和方法。 Objects and methods. Background technique [0006] The regeneratio...

Claims

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Application Information

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IPC IPC(8): C12N5/00C12N5/071
CPCC12N2501/15C12N2501/155C12N2501/727A61K38/05A61K31/519C12N5/0619A61K31/4439A61K31/506C12N2506/08C12N2501/999C12N2501/998A61K2300/00A61K31/00
Inventor 陈功吴冈义张磊殷久超叶怡君马宁馨格瑞斯·李
Owner PENN STATE RES FOUND
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