title: Factors secreted from dental pulp stem cells show multifaceted benefits for treating acute lung injury in mice.
abstract: OBJECTIVE
  Acute respiratory distress syndrome (ARDS) is a severe inflammatory disorder characterized by acute respiratory failure, resulting from severe, destructive lung inflammation and irreversible lung fibrosis. We evaluated the use of stem cells derived from human exfoliated deciduous teeth (SHEDs) or SHED-derived serum-free conditioned medium (SHED-CM) as treatments for bleomycin (BLM)-induced mice acute lung injury (ALI), exhibiting several pathogenic features associated with the human disease ARDS.
  
  
  METHODS
  Mice with BLM-induced ALI with or without SHED or SHED-CM treatment were examined for weight loss and survival. The lung tissue was characterized by histological and real-time quantitative polymerase chain reaction analysis. The effects of SHED-CM on macrophage differentiation in vitro were also assessed.
  
  
  RESULTS
  A single intravenous administration of either SHEDs or SHED-CM attenuated the lung injury and weight loss in BLM-treated mice and improved their survival rate. Similar recovery levels were seen in the SHEDs and SHED-CM treatment groups, suggesting that SHED improves ALI by paracrine mechanisms. SHED-CM contained multiple therapeutic factors involved in lung-regenerative mechanisms. Importantly, SHED-CM attenuated the BLM-induced pro-inflammatory response and generated an anti-inflammatory/tissue-regenerating environment, accompanied by the induction of anti-inflammatory M2-like lung macrophages. Furthermore, SHED-CM promoted the in vitro differentiation of bone marrow-derived macrophages into M2-like cells, which expressed high levels of Arginase1, CD206 and Ym-1.
  
  
  CONCLUSIONS
  Our results suggest that SHED-secreted factors provide multifaceted therapeutic effects, including a strong M2-inducing activity, for treating BLM-induced ALI. This work may open new avenues for research on stem cell-based ARDS therapies.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Wakayama
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Naozumi
authors.initials: N
authors.lastname: Hashimoto
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsushita
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kohki
authors.initials: K
authors.lastname: Matsubara
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: akihito@med.nagoya-u.ac.jp.
authors.forename: Akihito
authors.initials: A
authors.lastname: Yamamoto
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000628:therapy*; D000818:Animals; D001119:Arginase / Q000378:metabolism / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D002454:Cell Differentiation; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D003782:Dental Pulp / Q000166:cytology* / Q000378:metabolism; D005260:Female; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000166:cytology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D011956:Receptors, Cell Surface / Q000378:metabolism; D012038:Regeneration; D012128:Respiratory Distress Syndrome / Q000473:pathology / Q000628:therapy*; D033581:Stem Cell Transplantation; D014094:Tooth, Deciduous / Q000166:cytology* / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D001761:Bleomycin; C574619:ARG1 protein, human; D001119:Arginase
keywords: conditioned medium; dental pulp stem cells; inflammation; macrophages; respiratory distress syndrome