Generation of neural stem cells from human trophoblast stem cells
Inventors
Lee, Jau-Nan • Lee, Tony Tung-Ying • Lee, Yuta • Tsai, Eing-Mei
Assignees
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Publication Number
US-11254911-B2
Publication Date
2022-02-22
Expiration Date
Abstract
Provided herein are isolated neural stem cells. Also provided are methods for treatment of neurodegenerative diseases using suitable preparations comprising the isolated neural stem cells.
Core Innovation
The disclosed invention relates to isolated neural stem cells derived from human trophoblast stem cells for use in cell-based therapy of neurodegenerative and neuropsychiatric disorders. The neural stem cell population is generated such that reduced immunogenicity is achieved, with pluripotency and immune privilege-associated attributes. The material characterizes the neural stem cells using protein and transcript marker profiles including nestin, Oct4, Nanog, CD133, and immune-related markers such as low or absent CD33 and low CD133.
The invention further describes inducing differentiation from trophoblast stem cells into neural stem cells largely through retinoic acid and retinoic acid-related signaling pathways. The described signaling network includes RXRα/RARβ involvement, RALDH-2 and RALDH-3, GPCR/G-protein signaling including Gαq/11 and c-Src/Stat3/Nanog, Wnt2B/Fzd6/β-catenin, PI3K/Akt, NFAT1/calcineurin, CaMKII, and HDAC6 as part of the differentiation framework.
In vivo and cellular evidence summarized across figures supports that retinoic acid-induced differentiation shows differentiation consistency and immune marker comparisons versus hTS and hES. The disclosed outcomes include improved behavioral measures and regeneration marked by TH+ neurons in Parkinson’s disease rat models following tNSC transplantation, together with reduced tumorigenesis and reduced immune reactions in SCID model settings.
Claims Coverage
The provided claim coverage includes one independent claim. It defines a method to induce differentiation of a mammalian trophoblast stem cell into a neural stem cell population with reduced immunogenicity, with two principal inventive features tied to retinoic acid induction and specific immunogenicity marker outcomes.
Retinoic acid induction and timed contact to differentiate trophoblast stem cells into reduced-immunogenicity neural stem cells
Inducing a mammalian trophoblast stem cell to differentiate into a population of neural stem cells with reduced immunogenicity by contacting the trophoblast stem cell with an induction drug comprising retinoic acid before removing the induction drug, thereby differentiating into the neural stem cell population with reduced immunogenicity.
Uniform absence of CD33 and low CD133 protein expression after induction
Producing the population of neural stem cells such that the population uniformly has an absence of CD33 protein expression and a low level of CD133 protein expression compared to a mammalian trophoblast stem cell not contacted with the induction drug.
The coverage is centered on retinoic acid-based induction of trophoblast stem cell differentiation into neural stem cells, with reduced immunogenicity defined by uniform absence of CD33 protein expression together with low CD133 protein expression.
Stated Advantages
Reduced immunogenicity of the neural stem cell population, characterized by uniformly absent CD33 protein expression and low CD133 protein expression.
Improved behavioral outcomes and regeneration marked by TH+ neurons after tNSC transplantation in Parkinson’s disease rat models.
Reduced tumorigenesis and reduced immune reactions in SCID models.
Documented Applications
Cell-based therapy for neurodegenerative and neuropsychiatric disorders, exemplified by Parkinson’s disease rat models using tNSC transplantation.
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