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J Surg Res. 2019 Mar 4;239:191-200. doi: 10.1016/j.jss.2019.02.010. [Epub ahead of print]

Human Stem Cells Promote Liver Regeneration After Partial Hepatectomy in BALB/C Nude Mice.

Author information

1
Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany. Electronic address: simon.wabitsch@charite.de.
2
Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany.
3
Departement of Pathology, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany.
4
Apceth Biopharma GmbH, Munich, Germany.

Abstract

BACKGROUND:

Mesenchymal stem cells (MSCs) have been suggested to augment liver regeneration after surgically and pharmacologically induced liver failure. To further investigate this we processed human bone marrow-derived MSC according to good manufacturing practice (GMP) and tested those cells for their modulatory capacities of metabolic alterations and liver regeneration after partial hepatectomy in BALB/c nude mice.

METHODS:

Human MSCs were obtained by bone marrow aspiration of healthy donors as in a previously described GMP process. Transgenic GFP-MSCs were administered i.p. 24 h after 70% hepatectomy in BALB/c nude mice, whereas control mice received phosphate-buffered saline. Mice were sacrificed 2, 3, and 5 d after partial hepatectomy. Blood and organs were harvested and metabolic alterations as well as liver regeneration subsequently assessed by liver function tests, multianalyte profiling immunoassays, histology, and immunostaining.

RESULTS:

Hepatocyte and sinusoidal endothelial cell proliferation were significantly increased after partial hepatectomy in mice receiving MSC compared to control mice (Hepatocyte postoperative day 3, P < 0.01; endothelial cell postoperative day 5, P < 0.05). Hepatocyte fat accumulation correlated inversely with hepatocyte proliferation (r2 = 0.4064, P < 0.01) 2 d after partial hepatectomy, with mice receiving MSC being protected from severe fat accumulation. No GFP-positive cells could be detected in the samples. Serum levels of IL-6, HGF, and IL-10 were significantly decreased at day 3 in mice receiving MSC when compared to control mice (P < 0.05). Relative body weight loss was significantly attenuated after partial hepatectomy in mice receiving MSC (2 d and 3 d, both P < 0.001) with a trend toward a faster relative restoration of liver weight, when compared to control mice.

CONCLUSIONS:

Human bone marrow-derived MSC attenuate metabolic alterations and improve liver regeneration after partial hepatectomy in BALB/c nude mice. Obtained results using GMP-processed human MSC suggest functional links between fat accumulation and hepatocyte proliferation, without any evidence for cellular homing. This study using GMP-proceeded MSC has important regulatory implications for an urgently needed translation into a clinical trial.

KEYWORDS:

Hepatocyte proliferation; Liver regeneration; Mesenchymal stem cells; Partial hepatectomy; Stem cells

PMID:
30844633
DOI:
10.1016/j.jss.2019.02.010

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