Designer umbilical cord-stem cells induce alveolar wall regeneration in pulmonary disease models

Mayumi Iwatake; Tokiko Nagamura-Inoue; Ryoichiro Doi; Yukinori Tanoue; Mitsutoshi Ishii; Hiroshi Yukawa; Keitaro Matsumoto; Koichi Tomoshige; Takeshi Nagayasu; Tomoshi Tsuchiya

doi:10.3389/fimmu.2024.1384718

Designer umbilical cord-stem cells induce alveolar wall regeneration in pulmonary disease models

Front Immunol. 2024 Apr 30:15:1384718. doi: 10.3389/fimmu.2024.1384718. eCollection 2024.

Authors

Affiliations

¹ Institute of Nano-Life-Systems, Institutes of Innovation for Future Society, Nagoya University, Nagoya, Japan.
² Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
³ Department of Cell Processing and Transfusion, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁴ Department of Thoracic Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan.

Abstract

Background: Researchers are focusing on cellular therapy for chronic obstructive pulmonary disease (COPD) using mesenchymal stem cells (MSCs), with human bone marrow-derived MSCs (hBM-MSCs) leading the way. However, BM-MSCs may not be as optimal as therapeutic cells owing to their low growth potential, invasive harvesting, and high expression of aging-related genes with poor differentiation potential. Consequently, umbilical cord-derived MSCs (hUC-MSCs), which have many excellent features as allogeneic heterologous stem cells, have received considerable attention. Allogeneic and heterologous hUC-MSCs appear to be promising owing to their excellent therapeutic properties. However, MSCs cannot remain in the lungs for long periods after intravenous infusion.

Objective: To develop designer hUC-MSCs (dUC-MSCs), which are novel therapeutic cells with modified cell-adhesion properties, to aid COPD treatment.

Methods: dUC-MSCs were cultured on type-I collagen gels and laminin 411, which are extracellular matrices. Mouse models of elastase-induced COPD were treated with hUC-MSCs. Biochemical analysis of the lungs of treated and control animals was performed.

Results: Increased efficiency of vascular induction was found with dUC-MSCs transplanted into COPD mouse models compared with that observed with transplanted hUC-MSCs cultured on plates. The transplanted dUC-MSCs inhibited apoptosis by downregulating pro-inflammatory cytokine production, enhancing adhesion of the extracellular matrix to alveolar tissue via integrin β1, promoting the polarity of M2 macrophages, and contributing to the repair of collapsed alveolar walls by forming smooth muscle fibers. dUC-MSCs inhibited osteoclastogenesis in COPD-induced osteoporosis. hUC-MSCs are a promising cell source and have many advantages over BM-MSCs and adipose tissue-derived MSCs.

Conclusion: We developed novel designer cells that may be involved in anti-inflammatory, homeostatic, injury repair, and disease resistance processes. dUC-MSCs repair and regenerate the alveolar wall by enhancing adhesion to the damaged site. Therefore, they can contribute to the treatment of COPD and systemic diseases such as osteoporosis.

Keywords: COPD; cell adhesion; cellular therapy; macrophage; osteoporosis.

MeSH terms

Animals
Cell Differentiation
Cells, Cultured
Cord Blood Stem Cell Transplantation / methods
Disease Models, Animal*
Humans
Male
Mesenchymal Stem Cell Transplantation*
Mesenchymal Stem Cells* / metabolism
Mice
Mice, Inbred C57BL
Pulmonary Alveoli
Pulmonary Disease, Chronic Obstructive* / therapy
Regeneration*
Umbilical Cord / cytology

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study received financial support from Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (grant no. 20K10010 to MIw; grant no. 20K0255 to TT; and 21K08907 to MIs) and the Nagasaki University State of the Art Research program (TT).