title: Establishing Proximal and Distal Regional Identities in Murine and Human Tissue-Engineered Lung and Trachea.
abstract: The cellular and molecular mechanisms that underpin regeneration of the human lung are unknown, and the study of lung repair has been impeded by the necessity for reductionist models that may exclude key components. We hypothesized that multicellular epithelial and mesenchymal cell clusters or lung organoid units (LuOU) could be transplanted to recapitulate proximal and distal cellular structures of the native lung and airways. Transplantation of LuOU resulted in the growth of tissue-engineered lung (TELu) that contained the necessary cell types consistent with native adult lung tissue and demonstrated proliferative cells at 2 and 4 weeks. This technique recapitulated important elements of both mouse and human lungs featuring key components of both the proximal and distal lung regions. When LuOU were generated from whole lung, TELu contained key epithelial and mesenchymal cell types, and the origin of the cells was traced from both ActinGFPand SPCGFPdonors to indicate that the cells in TELu were derived from the transplanted LuOU. Alveolar epithelial type 2 cells (AEC2s), club cells, ciliated cells marked by beta-tubulin IV, alveolar epithelial type I cells, Sox-2-positive proximal airway progenitors, p63-positive basal cells, and CGRP-positive pulmonary neuroendocrine cells were identified in the TELu. The mesenchymal components of peribronchial smooth muscle and nerve were identified with a CD31-positive donor endothelial cell contribution to TELu vasculature. TELu successfully grew from postnatal tissues from whole murine and human lung, distal murine lung, as well as murine and human trachea. These data support a model of postnatal lung regeneration containing the diverse cell types present in the entirety of the respiratory tract.
authors: 1 Division of Pediatric Surgery, Children's Hospital Los Angeles , Los Angeles, California.|2 Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles , Los Angeles, California.
authors: Andrew
authors: A
authors: Trecartin
authors: 1 Division of Pediatric Surgery, Children's Hospital Los Angeles , Los Angeles, California.|2 Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles , Los Angeles, California.
authors: Soula
authors: S
authors: Danopoulos
authors: 1 Division of Pediatric Surgery, Children's Hospital Los Angeles , Los Angeles, California.|2 Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles , Los Angeles, California.
authors: Ryan
authors: R
authors: Spurrier
authors: 2 Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles , Los Angeles, California.|3 Division of Otolaryngology, Children's Hospital Los Angeles , Los Angeles, California.
authors: Hanaa
authors: H
authors: Knaneh-Monem
authors: 2 Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles , Los Angeles, California.
authors: Michael
authors: M
authors: Hiatt
authors: 2 Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles , Los Angeles, California.
authors: Barbara
authors: B
authors: Driscoll
authors: 2 Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles , Los Angeles, California.|3 Division of Otolaryngology, Children's Hospital Los Angeles , Los Angeles, California.|4 Keck School of Medicine, University of Southern California , Los Angeles, California.
authors: Christian
authors: C
authors: Hochstim
authors: 1 Division of Pediatric Surgery, Children's Hospital Los Angeles , Los Angeles, California.|2 Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles , Los Angeles, California.|4 Keck School of Medicine, University of Southern California , Los Angeles, California.
authors: Denise
authors: D
authors: Al-Alam
authors: 1 Division of Pediatric Surgery, Children's Hospital Los Angeles , Los Angeles, California.|2 Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles , Los Angeles, California.|4 Keck School of Medicine, University of Southern California , Los Angeles, California.
authors: Tracy C
authors: TC
authors: Grikscheit
mesh_terms: D000818:Animals; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D008168:Lung / Q000166:cytology* / Q000502:physiology; D016040:Lung Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D023822:Tissue Engineering / Q000379:methods*; D014132:Trachea / Q000166:cytology / Q000378:metabolism*; D014945:Wound Healing
keywords: adult stem cells; human; lung; mouse; tissue engineering; trachea