Chapman (UCSF) Research Hub 01

Harold (Hal) Chapman, MD

U01 Principal Investigator, 1-U01HL134766-01

Epithelial Stem/Progenitor Cells as Repair Agents in Diffuse Alveolar Damage

The overall goal of this application is to develop a compelling rationale and workable methodology for the treatment of diffuse alveolar damage with transplanted human epithelial stem/progenitor cells capable of long term engraftment and improved organ function. Stem/progenitor replacement therapy is envisioned as a meaningful therapeutic adjunct in several clinical situations dominated by diffuse alveolar damage with epithelial loss: severe, acute lung injury, e.g. due to influenza or other causes of ARDS, as well as acute exacerbations of chronic fibrotic lung disease. Recent studies discussed in the application indicate effective alveolar regeneration, and thus improved lung function, requires both a first phase of expansion and migration of stem/progenitor cells to re-establish alveolar barriers followed by a second phase of differentiation of new barrier cells into mature type II (AEC2s) and type I alveolar cells. To develop a translational program for alveolar regeneration by transplantation of healthy lung epithelial stem/progenitor cells, three basic objectives are advanced: (1) Further delineation of the signaling programs by which endogenous human distal lung epithelial stem cells can be activated following major injury to establish new alveolar barriers and then differentiate to AEC2s. (2) In vitro development of pools of human distal (small airway and alveolar) epithelial stem cells, both endogenous and iPSC-derived, suitable for transplantation and directed differentiation in mice. Distal basal-like cells from human iPS cells using gene edited cells reporting surfactant protein C, cytokeratin 17 (Krt17), and NKX2.1 will be used to develop a workable protocol for directed differentiation after transplant. (3) Employ models of lung repair/regeneration approachable by transplantation as tools to assess the regenerative potential of human epithelial stem/progenitor cells. Macaque iPS cells suitable for transplantation into influenza-infected monkeys will be used as a primate model for therapy. It is anticipated that functional improvement in gas exchange and alveolar histology can be achieved in primates, providing both a rationale and methodology for stem/progenitor cells as adjunctive therapy after severe acute lung injury in humans.

Lead Principal Investigator
User Name Full Name Institute Affiliation Topic tags People tags
hchapman's picture
hchapman Harold (Hal) Chapman, MD UCSF School of Medicine
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jrock's picture
jrock Jason Rock, PhD University of California
Post-Doctoral Fellow/Trainee
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kabo's picture
kabo Kristine M. Abo BU
KAalysandratos's picture
KAalysandratos Konstantinos Alysandratos M.D. Ph.D Boston University School of Medicine
mcohen's picture
mcohen Max Cohen UCSF Chapman Hub
jaja's picture
jaja Julio de Aja Harvard
eeverton's picture
eeverton Elissa Everton Boston University
fhawkins's picture
fhawkins Finn Hawkins, PhD USCF
jberthet's picture
jberthet Julia Hicks-Berthet BU
ohix's picture
ohix Olivia Hix BU
shon's picture
shon Stephanie Hon BU
hjess's picture
hjess Jessie Huang BU
Jkathiriya's picture
Jkathiriya Jaymin J Kathiriya Ph.D UCSF School of Medicine
ckubaczka's picture
ckubaczka Caroline Kubaczka BU
rwerder's picture
rwerder Rhiannon Bree Werder, Ph.D. Boston University School of Medicine
aysasi's picture
aysasi Alexandra Ysasi Boston University
Affiliated Investigator
User Name Full Name Institute Affiliation Topic tags People tags
dkotton's picture
dkotton Darrell Kotton, MD Boston University
lmiller's picture
lmiller Lisa A. Miller, Ph.D. UCSF
awilson's picture
awilson Andrew WIlson, PhD Boston University
Author(s) Title Link
Wei Y, Dong W, Jackson J, Ho TC, Le Saux CJ, Brumwell A et al. Blocking LOXL2 and TGFβ1 Signaling Induces Collagen Turnover in Precision-cut Lung Slices Derived from Patients with Idiopathic Pulmonary Fibrosis. view
Bota-Rabassedas N, Banerjee P, Niu Y, Cao W, Luo J, Xi Y et al. Contextual Clues from Cancer Cells Govern Cancer-associated Fibroblast Heterogeneity view
Kathiriya JJ, Wang C, Zhou M, Brumwell A, Cassandras M, Le Saux CJ, Cohen M, Alysandratos KD, Wang B, Wolter P, Matthay M, Kotton, DN, Chapman HA, Peng T. Human Alveolar Type 2 Epithelium Transdifferentiates into metaplastic KRT5+ Basal Cells view
Chapman HA, Wei Y, Montas G, Leong D, Golden JA, Trinh BN et al. Reversal of TGFβ1-Driven Profibrotic State in Patients with Pulmonary Fibrosis view
Kathiriya JJ, Brumwell AN, Jackson JR, Tang X, Chapman HA. Distinct Airway Epithelial Stem Cells Hide among Club Cells but Mobilize to Promote Alveolar Regeneration view
Katherine McCauley, Finn Hawkins, Darrell Kotton Efficient Derivation of Functional Human Airway Epithelium from Pluripotent Stem Cells via Temporal Regulation of Wnt Signaling view
Finn Hawkins,1,2 Philipp Kramer,3 Anjali Jacob,1,2 Ian Driver,4 Dylan C. Thomas,1 Katherine B. McCauley,1,2 Nicholas Skvir,1 Ana M. Crane,3 Anita A. Kurmann,1,5 Anthony N. Hollenberg,5 Sinead Nguyen,1 Brandon G. Wong,6 Ahmad S. Khalil,6,7 Sarah X.L. Huang,3,8 Susan Guttentag,9 Jason R. Rock,4 John M. Shannon,10 Brian R. Davis,3 and Darrell N. Kotton1,2 Prospective isolation of NKX2-1–expressing human lung progenitors derived from pluripotent stem cells view
Kanegai CM, Xi Y, Donne ML, Gotts JE, Driver IH, Amidzic G, Lechner AJ, Jones KD, Vaughan AE, Chapman HA, Rock JR. Am J Persistent Pathology in Influenza-Infected Mouse Lungs. view

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