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Methods of making tissues and organs

A production method and organ technology, applied in biochemical equipment and methods, tissue regeneration, tissue culture, etc., can solve the problems of not yet clearly established human tissue-organ remodeling method, organ transplant rejection, and non-existing methods, etc. Achieving the effect of high manufacturing technology value

Active Publication Date: 2019-05-17
PUBLIC UNIV CORP YOKOHAMA CITY UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are rejection reactions or absolute shortage of donors in organ transplantation, artificial organs can only replace part of the functions in a short period of time (JP-A-9-56814, JP-A-2004-166717), fundamental problems remain not solved
For the artificial production of human tissue, the method of inoculating terminally differentiated cells onto a carrier (scaffold material) has been examined, but for organs with complex and advanced functions such as the liver, the current situation is still unsatisfactory. There is no clearly established method (Non-Patent Document 1)
That is, the current situation is that a human tissue-organ reconstruction method that clearly establishes an ordered three-dimensional structure composed of multiple cell lineages seen in adult tissues has not yet been realized.

Method used

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  • Methods of making tissues and organs
  • Methods of making tissues and organs
  • Methods of making tissues and organs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] [Example 1] Fabrication of organs using undifferentiated organ cells

[0104] 〔experimental method〕

[0105] 【(1) Production of human liver endoderm cells】

[0106] Human iPS cells (human skin-derived TkDA3hiPSC clone (gifted from Koji Eto and Hiromitsu Nakauchi)) were cultured in a serum-free medium by adding activin to induce CXCR4- and E-cadherin-positive endoderm cells. By adding BMP4 and FGF2 to the obtained endoderm cells and culturing them for 2 days, a CXCR4-negative HNF4α-positive hepatic endoderm group was obtained. The expressions of CXCR4 and HNF4α were confirmed by immunostaining and gene expression analysis according to the description in Hepatology, 51(1), 297-305, 2010.

[0107] 【(2) Production of human liver buds】

[0108] The obtained hepatic endoderm cells were combined with vascular endothelial cells (human umbilical cord blood-derived venous endothelial cells) (Lonza, Basel, Switzerland) and undifferentiated mesenchymal cells (human mesenchymal s...

Embodiment 2

[0122] [Example 2] Fabrication of organs using differentiated organ cells

[0123] 〔experimental method〕

[0124] Mix pancreatic beta cell line (MIN6) with vascular endothelial cells (human umbilical cord blood-derived venous endothelial cells) and undifferentiated mesenchymal cells (human mesenchymal stem cells) at a ratio of 5:5-10:2 for co-culture . For the pancreatic β-cell line (KO) and vascular endothelial cells (EGFP), cells labeled with each fluorescent marker were used. For co-cultivation, the cell suspension was inoculated on a culture dish immobilized with matrigel (BD pharmingen) diluted 2 times from the stock solution. In addition, no three-dimensional structure was formed when embedded in matrigel, or in a non-coated or type 1 collagen-coated culture dish. As a culture medium, endothelial cell culture medium kit-2: EGM-2BulletKit (product code CC-3162: Lonza) was used.

[0125] Perform short-term (3-10 days) culture to produce three-dimensional structures. T...

Embodiment 3

[0135] [Example 3] Production of functional vascularized human liver transplanted from artificial pluripotent stem cell-derived organ buds

[0136] Donor organs are significantly scarce for the treatment of end-stage organ failure, using patient-derived artificial pluripotent stem cells (hiPSCs) 1，2 The need to make organs is increasing. Although multiple papers report functional cell differentiation 3-7 , there is no successful example in the preparation of an organ having a three-dimensional vascular network such as the liver. We have succeeded in generating functional human liver tissue with vascular structures by transplantation of in vitro produced hiPSC-derived liver buds (hiPSC-LBs). In addition to endothelial cells and mesenchymal cells 8Furthermore, iPS cell-derived hepatic endoderm cells self-organized with 3D hiPSC-LBs while promoting organogenesis. As a result of immunostaining and analysis of expressed genes, similarity was confirmed between hiPSC-LBs grown in...

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Abstract

The present invention provides means for reconstituting mature functional tissues and organs. A method for producing a tissue or organ, characterized in that organ cells are co-cultured with vascular endothelial cells and undifferentiated mesenchymal cells to produce organ buds, which are transplanted into non-human animals, and thereafter, the transplanted organs are taken out from the non-human animals The tissue or organ from which the buds originate.

Description

technical field [0001] The present invention relates to methods for producing organ buds, tissues, and organs from undifferentiated cells such as artificial pluripotent stem cells (iPS cells). Background technique [0002] In recent years, research and development by inducing differentiation of human functional cells useful for creative new drug screening or regenerative medicine using pluripotent stem cells such as iPS cells that have the ability to differentiate into various functional cells has attracted attention. Various attempts have been made to differentiate and induce cells with various functions by adding various inducing factors to the culture system of pluripotent stem cells (M. Schuldiner, et al. PNAS, 97 (21), 11307-11312 (2000), K. Si-Taiyeb, et al. Hepatology, 51(1):297-305 (2010)). However, in the conventional differentiation-inducing method that does not involve reconstruction of the three-dimensional tissue structure, it is difficult to induce terminal di...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12N5/00C12N5/10
CPCC12N5/0671C12N5/0677C12N2501/115C12N2501/12C12N2501/155C12N2502/1358C12N2502/28C12N2506/45C12N2533/54C12N2533/90A61K35/12A61K35/407A61K35/545A61L27/3808A61L27/3834A61L27/3886A61L27/3804A61L27/54A61L2300/412A61L2300/414A61L2430/26A61L2430/28A61P1/16A61P1/18A61K35/28A61K35/44C12N5/0697A01K2267/03A61K35/39A61K49/0008C12N2501/16
Inventor 谷口英树武部贵则
Owner PUBLIC UNIV CORP YOKOHAMA CITY UNIV
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