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Multiple Injections of Adipose-Derived Stem Cells Improve Graft Survival in Human-to-Rat Skin Xenotransplantation through Immune Modulation

  • Original Article
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Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Background:

Adipose-derived stem cells (ADSCs) exert immunomodulatory effects in the treatment of transplant rejection. This study aimed to evaluate the effects of ADSCs on the skin graft survival in a human-to-rat xenograft transplantation model and to compare single and multiple injections of ADSCs.

Methods:

Full-thickness human skin xenografts were transplanted into the backs of Sprague–Dawley rats. The rats were injected subcutaneously on postoperative days 0, 3, and 5. The injections were as follows: triple injections of phosphate-buffered saline (PBS group), a single injection of ADSCs and double injections of PBS (ADSC × 1 group), and triple injections of ADSCs (ADSC × 3 group). The immunomodulatory effects of ADSCs on human skin xenografts were assessed.

Results:

Triple injections of ADSCs considerably delayed cell-mediated xenograft rejection compared with the PBS and ADSC × 1 groups. The vascularization and collagen type 1–3 ratios in the ADSC × 3 group were significantly higher than those in the other groups. In addition, intragraft infiltration of CD3-, CD4-, CD8-, and CD68-positive cells was reduced in the ADSC × 3 group. Furthermore, in the ADSC × 3 group, the expression levels of proinflammatory cytokine interferon-gamma (IFN-γ) were decreased and immunosuppressive prostaglandin E synthase (PGES) was increased in the xenograft and lymph node samples.

Conclusion:

This study presented that triple injections of ADSCs appeared to be superior to a single injection in suppressing cell-mediated xenograft rejection. The immunomodulatory effects of ADSCs are associated with the downregulation of IFN-γ and upregulation of PGES in skin xenografts and lymph nodes.

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Acknowledgements

This research was supported and funded by Seoul National University Hospital (Grant Number: 0420203100).

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Author notes

  1. Sungmi Jeon and Iljin Kim have contributed equally to this work.

Authors and Affiliations

  1. Department of Plastic and Reconstructive Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea

    Sungmi Jeon, Ki Yong Hong, Hak Chang, Seung Hwan Kim, Yu Jin Jeong & Sang Wha Kim

  2. Department of Plastic and Reconstructive Surgery, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea

    Sungmi Jeon

  3. Department of Pharmacology and Program in Biomedical Science and Engineering, Inha University, Incheon, 22212, Republic of Korea

    Iljin Kim

  4. Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University Medical College, Seoul, Republic of Korea

    Yi Rang Na

  5. Transdisciplinary Department of Medicine and Advanced Technology, Seoul National University Hospital, Seoul, Republic of Korea

    Yi Rang Na

  6. Division of Pediatric Plastic Surgery, Seoul National University Children’s Hospital, Seoul, Republic of Korea

    Jee Hyeok Chung

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Contributions

S.W.K. and J.H.C. supervised the study; S.J. designed and performed the experiments with assistance from I.K., Y.R.N, K.Y.H, H.C., S.H.K., and Y.J.J.; S.J. and I.K. wrote the manuscript; and all authors commented on the manuscript.

Corresponding authors

Correspondence to Jee Hyeok Chung or Sang Wha Kim.

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The authors declare that they have no conflicts of interest. None of the authors have a financial interest in any of the products, devices, or drugs mentioned in this manuscript.

Ethical statement

All animal experiments were approved by the Institutional Animal Care and Use Committee of the Seoul National University Hospital (SNUH-IACUC no. 21-0143-S1A0). Informed consent was waived after approval by the Institutional Review Board of Seoul National University Hospital (no. 2021-3273).

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Supplementary Information

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Supplementary Figure S1. Primer sequences used for quantitative real-time PCR (PDF 43 KB)

13770_2023_552_MOESM2_ESM.pdf

Supplementary Figure S2. Characterization of adipose-derived stem cells. A Representative images of cell morphology under light microscope. Lower (left) and higher (right) magnification. Scale bar, 100 µm. C Flow cytometric analysis for mesenchymal (CD73 and CD90) and hematopoietic (CD11b and CD34) cell markers (PDF 707 KB)

13770_2023_552_MOESM3_ESM.pdf

Supplementary Figure S3. Long-term results of the skin xenografts until postoperative 8 weeks. A Representative images of the xenografts on POD 21, 28 and 56. Scale bar, 1 mm. B The human skin xenografts firmly attached to the rat tissue as dry scabs 8 weeks post operation (PDF 359 KB)

13770_2023_552_MOESM4_ESM.pdf

Supplementary Figure S4. Long-term histological results of the skin xenografts until 8 weeks. A Representative images of hematoxylin and eosin (H&E) and Masson’s trichome (MT) staining in low-power field (LPF) 8 weeks post operation. There were few noticeable differences between the PBS, ADSC × 1, and ADSC × 3 groups at the 8-week time point. Scale bar, 1 mm. B Representative images showing the contact layer between the human xenograft and rat tissue 8 weeks post operation. Regeneration of the rat-derived epithelium was limited to the peripheral rim of the xenografts, which suggests that the grafts did not fully integrate with the host tissue. Scale bar, 3 mm and 1 mm (for upper and lower row, respectively) (PDF 3755 KB)

13770_2023_552_MOESM5_ESM.pdf

Supplementary Figure S5. Immunohistochemistry staining for proliferating cell nuclear antigen (PCNA) in the epithelium of the skin xenografts on POD 10 and 14. PCNA-positive cells decreased with the advancement of rejection, accompanied by disorganization of the epidermis, in the PBS group followed by the ADSC × 1 and ADSC × 3 groups. Scale bar, 50 μm. PBS, phosphate-buffered saline; ADSC, adipose-derived stem cell; POD, postoperative day (PDF 328 KB)

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Jeon, S., Kim, I., Na, Y.R. et al. Multiple Injections of Adipose-Derived Stem Cells Improve Graft Survival in Human-to-Rat Skin Xenotransplantation through Immune Modulation. Tissue Eng Regen Med 20, 905–919 (2023). https://doi.org/10.1007/s13770-023-00552-x

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