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Cell reprogramming

A cell and target cell technology, applied in the field of cell reprogramming, can solve the problems of difficult identification of elements, unknown factors, and limited identification of factors that directly reprogram cell type identities

Pending Publication Date: 2018-12-21
重组生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While it is possible to switch the phenotype of one somatic cell type to another, the elements required for switching are difficult to identify and in most cases unknown
Among other things, the identification of factors that directly reprogram cell-type identity is currently limited by the cost of exhaustive experimental testing of plausible sets of factors, an inefficient and non-scalable approach

Method used

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Examples

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example 1

[0406] To predict the set of TFs required for each cell transition, we identified those TFs that were not only differentially expressed between cell types but also exerted regulatory influence on other differentially expressed genes in local networks (see figure 1 a). A single score capturing the differential expression of each gene in each cell type was defined by combining log fold changes and adjusted p-values. By analyzing the known interactome (as defined by STRING and MARA, see figure 1 c) A weighted summation of differential expression scores was performed to calculate the regulatory impact of each TF in each cell type. This sum is weighted by two factors: (1) immediacy by regulation, i.e. how many intermediates are between the TF and downstream genes, and (2) specificity, i.e. the number of other genes that the upstream TF also regulates. This weighted sum allows ranking of TFs in each cell type according to their influence. The final step is to select the best set ...

example 2

[0445] To assess the predictive power of Mogrify, we first determined how Mogrify counteracts well-known previously published direct cell transformations, focusing on those involving human cells. These should not be considered as absolute perfect combinations, but as positive reference points that can be used for comparison. Such as figure 2 As shown, in almost every case, Mogrify predicts the full set of TFs previously shown to work, but sometimes includes upstream TFs in place of published factors. For example, it is known that human fibroblasts can be converted into iPS cells by introducing OCT4 (also called POU5F1), SOX2, KLF4, and MYC, or OCT4, SOX2, NANOG, and LIN28. Mogrify predicts NANOG, OCT4, and SOX2 as the top 3 TFs for this transition, a combination that has also been experimentally validated. Previous work has demonstrated that expression of CEBPa and PU.1 (also known as SPI1) can switch B cells and fibroblasts into macrophage-like cells (Xie, H., Ye, M., Feng...

example 3

[0466] To empirically demonstrate the predictive power of Mogrify, we performed 11 novel cellular transformations using human cells:

[0467] Fibroblasts to keratinocytes (results in Example 4);

[0468] Keratinocytes to endothelial cells (results in Example 5);

[0469] Fibroblasts to endothelial cells (results in Example 6);

[0470] Embryonic stem cells to endothelial cells (results in Example 7);

[0471] Induced pluripotent stem cells to endothelial cells (results in Example 8);

[0472] Fibroblasts to astrocytes (results in Example 9);

[0473] Embryonic stem cells to astrocytes (results in Example 10);

[0474] Induced pluripotent stem cells to astrocytes (results in Example 11);

[0475] Bone mesenchymal stem cells to astrocytes (results in Example 12);

[0476] Embryonic stem cells to keratinocytes (results in Example 13); and

[0477] • Induction of pluripotent stem cells to keratinocytes (results in Example 14).

[0478] Materials and methods are described i...

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Abstract

The invention relates to methods and compositions for converting one cell type to another cell type. Specifically, the invention relates to transdifferentiation of a cell to a different cell type. Theinvention relates to a method for determining the transcription factors required for conversion of a source cell to a cell exhibiting at least one characteristic of a target cell type. The inventionalso relates to method of reprogramming or forward programming a source cell.

Description

[0001] This application claims priority from Australian Provisional Application AU 2015905349, the entire disclosure of which is incorporated herein in its entirety. technical field [0002] The present invention relates to methods and compositions for switching one cell type to another. Specifically, the present invention relates to the transdifferentiation of cells into different cell types. Background technique [0003] Cell-based regenerative therapies require the generation of specific cell types to replace tissue damaged by injury, disease or age. Embryonic stem cells (ESCs) have the potential to differentiate each cell type in vivo and have therefore been extensively studied as a source for alternative therapies. However, ESCs cannot be derived in a patient-specific manner as they are established from cultured blastocysts. Therefore, immune rejection and ethical issues are the main obstacles preventing the transfer of ESC technology (and human ESC technology in part...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N5/10C12N5/12C12N5/071C12N5/02C12N5/0735C12N5/0786C12N5/0783C12N5/0789C12N5/0775C12N5/077G16B5/20G16B30/00
CPCC12N2501/60C12N2510/00C12N2506/1307G16B5/00G16B30/00C12N5/0696G16B5/20G16B25/10C12N5/0663C12N5/0667C12N15/867
Inventor 哈韦尔·菲拉斯乔斯·波洛朱利安·高夫林崎良英欧文·拉克姆
Owner 重组生物科技有限公司
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