Dissecting Engineered Cell Types and Enhancing Cell Fate Conversion via CellNet

被引：198

作者：

Morris, Samantha A. ^{[1
,2
,3
,4
]}

Cahan, Patrick ^{[1
,2
,3
,4
]}

Li, Hu ^{[5
]}

Zhao, Anna M. ^{[1
,2
,3
,4
]}

Roman, Adrianna K. San ^{[6
,7
,8
]}

Shivdasani, Ramesh A. ^{[6
,7
,8
]}

Collins, James J. ^{[9
,10
,11
]}

Daley, George Q. ^{[1
,2
,3
,4
]}

机构：

[1] Boston Childrens Hosp, Howard Hughes Med Inst, Manton Ctr Orphan Dis Res, Div Pediat Hematol & Oncol,Stem Cell Transplantat, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[4] Harvard Stem Cell Inst, Cambridge, MA 02138 USA

[5] Mayo Clin, Coll Med, Ctr Individualized Med, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN 55905 USA

[6] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[7] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[8] Harvard Univ, Sch Med, Boston, MA 02115 USA

[9] Harvard Univ, Sch Med, Program Biol & Biomed Sci, Boston, MA 02115 USA

[10] Boston Univ, Howard Hughes Med Inst, Dept Biomed Engn, Boston, MA 02215 USA

[11] Harvard Univ, Wyss Inst Biologically Inspired Engn, Boston, MA 02215 USA

来源：

CELL | 2014年 / 158卷 / 04期

关键词：

TRANSCRIPTION FACTOR CDX2; DEFINED FACTORS; MOUSE FIBROBLASTS; FUNCTIONAL-NEURONS; STEM-CELLS; IDENTITY; TRANSPLANTATION; REGENERATION; HEPATOCYTES; BINDING;

D O I：

10.1016/j.cell.2014.07.021

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Engineering clinically relevant cells in vitro holds promise for regenerative medicine, but most protocols fail to faithfully recapitulate target cell properties. To address this, we developed CellNet, a network biology platform that determines whether engineered cells are equivalent to their target tissues, diagnoses aberrant gene regulatory networks, and prioritizes candidate transcriptional regulators to enhance engineered conversions. Using CellNet, we improved B cell to macrophage conversion, transcriptionally and functionally, by knocking down predicted B cell regulators. Analyzing conversion of fibroblasts to induced hepatocytes (iHeps), CellNet revealed an unexpected intestinal program regulated by the master regulator Cdx2. We observed long-term functional engraftment of mouse colon by iHeps, thereby establishing their broader potential as endoderm progenitors and demonstrating direct conversion of fibroblasts into intestinal epithelium. Our studies illustrate how CellNet can be employed to improve direct conversion and to uncover unappreciated properties of engineered cells.

引用

页码：889 / 902

页数：14

共 33 条

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