Generation of Functional Hepatocytes from Human Adipose-Derived MYC+ KLF4+ GMNN+ Stem Cells Analyzed by Single-Cell RNA-Seq Profiling

Hongling Li, Li Zhu, Huimin Chen, Tangping Li, Qin Han, Shihua Wang, Xinglei Yao, Hongli Feng, Linyuan Fan, Shaorong Gao, Richard Boyd, Xu Cao, Ping Zhu, Jing Li, Armand Keating, Xiaodong Su, Robert Chunhua Zhao

Research output: Contribution to journalArticle

Abstract

Cell transplantation holds considerable promise for end-stage liver diseases but identifying a suitable, transplantable cell type has been problematic. Here, we describe a novel type of mesenchymal stem cells (MSCs) from human adipose tissue. These cells are different from previously reported MSCs, they are in the euchromatin state with epigenetic multipotency, and express pluripotent markers MYC, KLF4, and GMNN. Most of the genes associated with germ layer specification are modified by H3K4me3 or co-modified by H3K4me3 and H3K27me3. We named this new type of MSCs as adult multipotent adipose-derived stem cells (M-ADSCs). Using a four-step nonviral system, M-ADSCs can be efficiently Induced into hepatocyte like cells with expression of hepatocyte markers, drug metabolizing enzymes and transporters, and the other basic functional properties including albumin (ALB) secretion, glycogen storage, detoxification, low-density lipoprotein intake, and lipids accumulation. In vivo both M-ADSCs-derived hepatoblasts and hepatocytes could form vascularized liver-like tissue, secrete ALB and express metabolic enzymes. Single-cell RNA-seq was used to investigate the important stages in this conversion. M-ADSCs could be converted to a functionally multipotent state during the preinduction stage without undergoing reprogramming process. Our findings provide important insights into mechanisms underlying cell development and conversion. Stem Cells Translational Medicine 2018;1–14.

Original languageEnglish (US)
JournalStem cells translational medicine
DOIs
Publication statusAccepted/In press - Jan 1 2018

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Keywords

  • Adult stem cell
  • Hepatocyte
  • Lineage conversion
  • Multipotency
  • Single-cell RNA-seq

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

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