J Korean Surg Soc.  2011 Sep;81(3):176-186. 10.4174/jkss.2011.81.3.176.

Therapeutic potential of adipose tissue-derived stem cells for liver failure according to the transplantation routes

• Kim SJ
• Park KC
• Lee JU
• Kim KJ
• Kim DG

• KMID: 2212195
• DOI: http://doi.org/10.4174/jkss.2011.81.3.176

Abstract

PURPOSE
Even though adipose tissue-derived stem cells (ADSCs) have been spotlighted as a possible alternative for liver transplantation in an experimental setting, the mechanism by which ADSCs improve liver dysfunction remains poorly characterized. The objective of this study was to evaluate the therapeutic ability of undifferentiated ADSCs, and find a few clues on how ADSCs alleviate liver damage by comparing the transplantation routes.
METHODS
In vitro generated human ADSCs were checked for surface markers and stage-specific genes for characterization. Afterwards, they were transplanted into C57BL/6 mice with CCl4-induced liver injury. The transplantations were made via tail vein, portal vein, and direct liver parenchymal injection. At 1 and 3 post-transplantation days, serum biochemical parameters and/or liver specimens were evaluated.
RESULTS
We have shown here that ADSCs have the characteristics of mesenchymal stem cells, and belong to endodermal and/or early hepatic differentiation stage. After transplantation into the mice with acute liver failure, markers of liver injury, such as alanineaminotransferase, aspartateaminotransferase, as well as ammonia, decreased. Of these transplantation routes, transplantation via tail vein rendered the most prominent reduction in the biochemical parameters.
CONCLUSION
Undifferentiated ADSCs have the ability to improve hepatic function in mice with acute liver injury. Moreover, our transplantation route study supports the theory that ADSCs in systemic circulation can exert endocrine or paracrine effects to ameliorate the injured liver.

Keyword

Adipose tissue-derived stem cell; Mesenchymal stem cells; Acute liver injury; Stem cell transplantation

MeSH Terms

Ammonia
Animals
Endoderm
Humans
Liver
Liver Diseases
Liver Failure
Liver Failure, Acute
Liver Transplantation
Mesenchymal Stromal Cells
Mice
Portal Vein
Stem Cell Transplantation
Stem Cells
Transplants
Veins
Ammonia

Figure

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  Fig. 1 Study design. SL, saline infusion via tail vein; PV, transplantation via portal vein; TV, transplantation via tail vein; LP, transplantation via direct liver parenchyma infusion.

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  Fig. 2 Morphology of adipose tissue-derived stem cells (ADSCs) before (A) and after (B) endodermal induction (×100 magnification). ADSCs initially had spindle-like appearance progressively changing into an oval shape after endodermal induction.

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  Fig. 3 Flow cytometry of adipose tissue-derived stem cells (ADSCs) with mesenchymal and hematopoietic stem cell markers. Mesenchymal stem cell markers (CD29, CD105, and CD166) were expressed whereas hematopoietic stem cell marker (CD34) was not.

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  Fig. 4 Genes related to hepatic differentiation determined by reverse transcription-polymerase chain reaction. Adipose-tissue derived stem cells (ADSCs), both before and after the endodermal induction, expressed GATA4, FOXA2, and AFP genes, and did not express albumin and HNF-4α genes.

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  Fig. 5 Engulfment of 4, 6-diamidino-2-phenylindole (DAPI)-labeled adipose tissue-derived stem cells (ADSCs) in mouse liver according to different transplantation routes. Mice with acute liver injury were transplanted with DAPI-labeled ADSCs injected through tail vein (TV group) (A), portal vein (PV group) (B), and direct liver parenchyma (LP group) (C). Panels show fluorescent microscopic views of representative liver sections obtained one day after the transplantation (×100 magnification). The number of DAPI-positive cells of the TV group was comparable to the number of the PV group (D). However, the number of DAPI- positive cells of the TV group was significantly higher than that of the LP group (P = 0.026).a)

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  Fig. 6 Comparison of histological changes according to transplantation routes. The histological sections were stained into two ways; H&E stain (A-D) and Ki67 immunohistochemical stain (E-H). Panel (A-D) represents the changes in the centrilobular necrosis area (red ellipse) observed after the saline infusion via tail vein (A), the transplantion of ADSCs via tail vein (B), portal vein (C), and direct liver parenchyma infusion (D). Panel (E-H) represents the changes in the occurrence of Ki67-positive nuclei (arrow; brown spot) observed after the saline infusion via tail vein (A), the transplantion of ADSCs via tail vein (B), portal vein (C), and direct liver parenchyma infusion (D).

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  Fig. 7 Comparison of biochemical parameters including aspartate aminotransferase (AST) (A), alanine aminotransferase (ALT) (B), and ammonia (C) according to transplantation routes. The means and standard deviations were demonstrated. Of the 3 different transplantation route groups, the TV group (adipose tissue-derived stem cells transplantation via tail vein) showed the most prominent reduction in the AST and ALT values (P<0.05). SL, saline infusion group; PV, transplantation via portal vein; TV, transplantation via tail vein; LP, transplantation via liver parenchyma.

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