Treatment with placenta-derived mesenchymal stem cells mitigates development of bronchiolitis obliterans in a murine model.

Abstract

OBJECTIVE:

Bone marrow-derived mesenchymal stem cells (MSCs) have shown therapeutic potential in acute lung injury. Recently, placenta-derived human mesenchymal stem cells (PMSCs) have shown similarities with bone marrow-derived MSCs in terms of regenerative capabilities and immunogenicity. This study investigates the hypothesis that treatment with PMSCs reduces the development of bronchiolitis obliterans in a murine heterotopic tracheal transplant model.

METHODS:

A murine heterotopic tracheal transplant model was used to study the continuum from acute to chronic rejection. In the treatment groups, PMSCs or PMSC-conditioned medium (PMSCCM) were injected either locally or intratracheally into the allograft. Phosphate-buffered saline (PBS) or blank medium was injected in the control groups. Tracheal luminal obliteration was assessed on sections stained with hematoxylin and eosin. Infiltration of inflammatory and immune cells and epithelial progenitor cells was assessed using immunohistochemistry and densitometric analysis.

RESULTS:

Compared with injection of PBS, local injection of PMSCs significantly reduced luminal obliteration at 28 days after transplantation (P = .015). Intratracheal injection of PMSCs showed similar results to local injection of PMSCs compared with injection of PBS and blank medium (P = .022). Tracheas treated with PMSC/PMSCCM showed protection against the loss of epithelium on day 14, with an increase in P63+CK14+ epithelial progenitor cells and Foxp3+ regulatory T cells. In addition, injection of PMSCs and PMSCCM significantly reduced the number of neutrophils and CD3+ T cells on day 14.

CONCLUSIONS:

This study demonstrates that treatment with PMSCs is protective against the development of bronchiolitis obliterans in an heterotopic tracheal transplant model. These results indicate that PMSCs could provide a novel therapeutic option to reduce chronic rejection after lung transplant.

• Authors: Yunge Zhao, Jacob R Gillen, David A Harris, Irving L Kron, Michael P Murphy, Christine L Lau
• Journal: The Journal of thoracic and cardiovascular surgery (J Thorac Cardiovasc Surg) Vol. 147 Issue 5 Pg. 1668-1677.e5 (May 2014) ISSN: 1097-685X [Electronic] United States
• PMID: 24199758 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Mosby, Inc.

Chemical References

• Biomarkers
• CD3 Complex
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• KRT14 protein, human
• Keratin-14
• TP63 protein, human
• Transcription Factors
• Tumor Suppressor Proteins

Topics

• Acute Disease
• Animals
• Biomarkers (metabolism)
• Bronchiolitis Obliterans (immunology, metabolism, pathology, prevention & control)
• CD3 Complex (metabolism)
• Cells, Cultured
• Chemotaxis, Leukocyte
• Chronic Disease
• Disease Models, Animal
• Disease Progression
• Epithelial Cells (immunology, metabolism, pathology, transplantation)
• Female
• Forkhead Transcription Factors (metabolism)
• Graft Rejection (immunology, metabolism, pathology, prevention & control)
• Humans
• Keratin-14 (metabolism)
• Macrophages (immunology, metabolism)
• Male
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Neutrophil Infiltration
• Placenta (cytology)
• Pregnancy
• T-Lymphocytes, Regulatory (immunology, metabolism)
• Time Factors
• Trachea (immunology, metabolism, pathology, transplantation)
• Transcription Factors (metabolism)
• Tumor Suppressor Proteins (metabolism)