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Multipotent Adipose‐derived Stem Cells: A Novel Stem Cell Source for Functional Hepatocytes?

Review of “Generation of Functional Hepatocytes from Human Adipose-derived MYC+ KLF4+ GMNN+ Stem Cells Analyzed by Single-cell RNA-Seq Profiling” from STEM CELLS Translational Medicine by Stuart P. Atkinson 

Hepatocytes form around 70 to 85% of the liver's mass and they play multiple crucial roles, including the detoxification, modification, and excretion of exogenous and endogenous substances. The differentiation of these highly utile cells from stem cells represents a possible means of supplying sufficient numbers of hepatocytes require to treat the over 500 million cases of chronic liver disease worldwide. While studies have established that bone marrow mesenchymal stem cells (MSCs) [1] or adipose-derived MSCs (ADSCs) [2] display the potential to regenerate human liver, their in vivo efficiency remains low [3, 4]. 

As a possible solution to this problem, recent through provoking research has evidenced the plasticity of a novel population termed adult multipotent adipose‐derived stem cells (M‐ADSCs), which can give rise to functional neuronal cells [5] and insulin‐secreting cells [6] with high efficiency. Now, a new STEM CELLS Translational Medicine study from the laboratories of Armand Keating, Xiaodong Su, and Robert Chunhua Zhao describes a four‐stage non‐virus methodology to generate functional hepatocyte-like cells from M‐ADSCs and reports on a single cell RNA-sequencing study of the cells that define the molecular events that control liver regeneration [7].

AD-MSCs differ from MSCs in that they express the pluripotency-associated MYC, KLF4, and GMNN lineage specifiers and display an epigenetic state compatible with multipotency, with most germ layer specification genes marked by H3K4me3 or co‐modified by H3K4me3 and H3K27me3 (so called-bivalent domains). Li et al. discovered that in addition to neuronal cells and insulin‐secreting cells, they could also coax AD-MSCs into hepatocyte-like cells in under three weeks through the application of a four‐step (initiation, stage 2, stage 3, and post-induction) strategy comprising the activation/inhibition of signaling pathways involved in embryonic liver development.

This approach generated cells that expressed hepatocyte markers, drug metabolizing enzymes and transporters, and displayed basic functional properties of hepatocytes, including albumin secretion, glycogen storage, detoxification, low‐density lipoprotein intake, and lipid accumulation. Excitingly, when the authors transplanted M‐ADSCs‐derived hepatoblasts and hepatocytes into nude mice, the vascularized liver‐like tissue that formed secreted albumin, and expressed metabolic enzymes.

The second part of this study employed single‐cell RNA‐seq to investigate the crucial stages of M‐ADSCs conversion into hepatocyte-like cells. Overall, the authors fully described the critical differentiation stages and discovered that the induction step caused M‐ADSCs to synchronize, convert into a functionally multipotent status, and then directly transition into the mesendodermal stage. Of note, this transpired without the need to pass into a reprogrammed pluripotent state before progressive specialization into the hepatic lineage.  

The authors of this fantastic new study do note that their cells may not be as mature as required, and so, they now hope to accelerate their research into optimized culture conditions to generate mature and stable M‐ADSCs‐derived hepatocyte-like cells.

For more on the burgeoning promise of multipotent adipose‐derived stem cells and in vitro derived hepatocyte-like cells, stay tuned to the Stem Cells Portal!


  1. Theise ND, Nimmakayalu M, Gardner R, et al., Liver from bone marrow in humans. Hepatology 2000;32:11-6.
  2. Banas A, Teratani T, Yamamoto Y, et al., Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytes. Hepatology 2007;46:219-28.
  3. Wang X, Willenbring H, Akkari Y, et al., Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 2003;422:897-901.
  4. Vassilopoulos G, Wang PR, and Russell DW, Transplanted bone marrow regenerates liver by cell fusion. Nature 2003;422:901-4.
  5. Feng N, Han Q, Li J, et al., Generation of highly purified neural stem cells from human adipose-derived mesenchymal stem cells by Sox1 activation. Stem Cells Dev 2014;23:515-29.
  6. Li J, Zhu L, Qu X, et al., Stepwise differentiation of human adipose-derived mesenchymal stem cells toward definitive endoderm and pancreatic progenitor cells by mimicking pancreatic development in vivo. Stem Cells Dev 2013;22:1576-87.
  7. Li H, Zhu L, Chen H, et al., Generation of Functional Hepatocytes from Human Adipose-Derived MYC+ KLF4+ GMNN+ Stem Cells Analyzed by Single-Cell RNA-Seq Profiling. STEM CELLS Translational Medicine 2018;7:792-805.