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Antifibrotic effect of lung-resident progenitor cells with high aldehyde dehydrogenase activity.

ABSTRACT:

Background

Aldehyde dehydrogenase (ALDH) is highly expressed in stem/progenitor cells in various tissues, and cell populations with high ALDH activity (ALDH^br) are associated with tissue repair. However, little is known about lung-resident ALDH^br. This study was performed to clarify the characteristics of lung-resident ALDH^br cells and to evaluate their possible use as a tool for cell therapy using a mouse model of bleomycin-induced pulmonary fibrosis.

Methods

The characteristics of lung-resident/nonhematopoietic (CD45^-) ALDH^br cells were assessed in control C57BL/6 mice. The kinetics and the potential usage of CD45^-/ALDH^br for cell therapy were investigated in bleomycin-induced pulmonary fibrosis. Localization of transferred CD45^-/ALDH^br cells was determined using mCherry-expressing mice as donors. The effects of aging on ALDH expression were also assessed using aged mice.

Results

Lung CD45^-/ALDH^br showed higher proliferative and colony-forming potential than cell populations with low ALDH activity. The CD45^-/ALDH^br cell population, and especially its CD45^-/ALDH^br/PDGFRα⁺ subpopulation, was significantly reduced in the lung during bleomycin-induced pulmonary fibrosis. Furthermore, mRNA expression of ALDH isoforms was significantly reduced in the fibrotic lung. When transferred in vivo into bleomycin-pretreated mice, CD45^-/ALDH^br cells reached the site of injury, ameliorated pulmonary fibrosis, recovered the reduced expression of ALDH mRNA, and prolonged survival, which was associated with the upregulation of the retinol-metabolizing pathway and the suppression of profibrotic cytokines. The reduction in CD45^-/ALDH^br/PDGFRα⁺ population was more remarkable in aged mice than in young mice.

Conclusions

Our results strongly suggest that the lung expression of ALDH and lung-resident CD45^-/ALDH^br cells are involved in pulmonary fibrosis. The current study signified the possibility that CD45^-/ALDH^br cells could find application as novel and useful cell therapy tools in pulmonary fibrosis treatment.

SUBMITTER: Takahashi H

PROVIDER: S-EPMC8381511 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Uncompromised by chronic disease-related comorbidities, human umbilical cord blood (UCB) progenitor cells with high aldehyde dehydrogenase activity (ALDHhi cells) stimulate blood vessel regeneration after intra-muscular transplantation. However, implementation of cellular therapies using UCB ALDHhi cells for critical limb ischemia, the most severe form of severe peripheral artery disease, is limited by the rarity (<0.5%) of these cells. Our goal was to generate a clinically-translatable, allogeneic cell population for vessel regenerative therapies, via ex vivo expansion of UCB ALDHhi cells without loss of pro-angiogenic potency. Purified UCB ALDHhi cells were expanded >18-fold over 6-days under serum-free conditions. Consistent with the concept that ALDH-activity is decreased as progenitor cells differentiate, only 15.1% ± 1.3% of progeny maintained high ALDH-activity after culture. However, compared to fresh UCB cells, expansion increased the total number of ALDHhi cells (2.7-fold), CD34+ /CD133+ cells (2.8-fold), and hematopoietic colony forming cells (7.7-fold). Remarkably, injection of expanded progeny accelerated recovery of perfusion and improved limb usage in immunodeficient mice with femoral artery ligation-induced limb ischemia. At 7 or 28 days post-transplantation, mice transplanted with expanded ALDHhi cells showed augmented endothelial cell proliferation and increased capillary density compared to controls. Expanded cells maintained pro-angiogenic mRNA expression and secreted angiogenesis-associated growth factors, chemokines, and matrix modifying proteins. Coculture with expanded cells augmented human microvascular endothelial cell survival and tubule formation under serum-starved, growth factor-reduced conditions. Expanded UCB-derived ALDHhi cells represent an alternative to autologous bone marrow as an accessible source of pro-angiogenic hematopoietic progenitor cells for the refinement of vascular regeneration-inductive therapies. Stem Cells Translational Medicine 2017;6:1607-1619.