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Organ-Specific Differentiation of Human Adipose-Derived Stem Cells in Various Organs of Xenotransplanted Rats: A Pilot Study.

ABSTRACT: Adipose-derived stem cells (ADSCs) are potential therapeutics considering their self-renewal capacity and ability to differentiate into all somatic cell types in vitro. The ideal ADSC-based therapy is a direct injection into the relevant organs. The objective of this study was to investigate the viability and safety of intra-organ human ADSC (h-ADSC) xenotransplants in vivo. Subcutaneous adipose tissue from the abdominal area of 10 patients was sampled. h-ADSCs were isolated from adipose tissue samples and identified using immunofluorescence antibodies. Multi-differentiation potential assays for adipocytes, osteocytes, and chondrocytes were performed. Cultured h-ADSCs at passage 4 were transplanted into multiple organs of 17 rats, including the skin, subcutaneous layer, liver, kidney, pancreas, and spleen. The h-ADSC-injected organs excised after 100 days were examined, and the survival of h-ADSCs was measured by quantitative real-time polymerase chain reaction (qRT-PCR) using specific human and rat target genes. h-ADSCs confirmed by stem cell phenotyping were induced to differentiate into adipogenic, osteogenic, and chondrogenic lineages in vitro. All rats were healthy and exhibited no side effects during the study; the transplanted h-ADSCs did not cause inflammation and were indiscernible from the native organ cells. The presence of transplanted h-ADSCs was confirmed using qRT-PCR. However, the engrafted survival rates varied as follows: subcutaneous fat (70.6%), followed by the liver (52.9%), pancreas (50.0%), kidney (29.4%), skin (29.4%), and spleen (12.5%). h-ADSCs were successfully transplanted into a rat model, with different survival rates depending on the organ.

SUBMITTER: Park JH

PROVIDER: S-EPMC9330795 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Human adipose-derived stem cells (ASCs) may differentiate into cardiomyocytes and this provides a source of donor cells for tissue engineering. In this study, we evaluated cardiomyogenic differentiation protocols using a DNA demethylating agent 5-azacytidine (5-aza), a modified cardiomyogenic medium (MCM), a histone deacetylase inhibitor trichostatin A (TSA) and co-culture with neonatal rat cardiomyocytes. 5-aza treatment reduced both cardiac actin and TropT mRNA expression. Incubation in MCM only slightly increased gene expression (1.5- to 1.9-fold) and the number of cells co-expressing nkx2.5/sarcomeric alpha-actin (27.2% versus 0.2% in control). TSA treatment increased cardiac actin mRNA expression 11-fold after 1 week, which could be sustained for 2 weeks by culturing cells in cardiomyocyte culture medium. TSA-treated cells also stained positively for cardiac myosin heavy chain, alpha-actin, TropI and connexin43; however, none of these treatments produced beating cells. ASCs in non-contact co-culture showed no cardiac differentiation; however, ASCs co-cultured in direct contact co-culture exhibited a time-dependent increase in cardiac actin mRNA expression (up to 33-fold) between days 3 and 14. Immunocytochemistry revealed co-expression of GATA4 and Nkx2.5, alpha-actin, TropI and cardiac myosin heavy chain in CM-DiI labelled ASCs. Most importantly, many of these cells showed spontaneous contractions accompanied by calcium transients in culture. Human ASC (hASC) showed synchronous Ca(2+) transient and contraction synchronous with surrounding rat cardiomyocytes (106 beats/min.). Gap junctions also formed between them as observed by dye transfer. In conclusion, cell-to-cell interaction was identified as a key inducer for cardiomyogenic differentiation of hASCs. This method was optimized by co-culture with contracting cardiomyocytes and provides a potential cardiac differentiation system to progress applications for cardiac cell therapy or tissue engineering.

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Organ-Specific Differentiation of Human Adipose-Derived Stem Cells in Various Organs of Xenotransplanted Rats: A Pilot Study.

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