2. Academic Validation
  3. Protease inhibitor Camostat Mesyalte blocks wild type SARS-CoV-2 and D614G viral entry in human engineered miniature lungs

Protease inhibitor Camostat Mesyalte blocks wild type SARS-CoV-2 and D614G viral entry in human engineered miniature lungs

  • Biomaterials. 2022 Jun;285:121509. doi: 10.1016/j.biomaterials.2022.121509.
Tong Wu 1,  Seyed A Rabi 2,  William A Michaud 3,  David Becerra 4,  Sarah E Gilpin 5,  Mari Mino-Kenudson 6,  Harald C Ott 7
Affiliations

Affiliations

  • 1 Massachusetts General Hospital, Center for Regenerative Medicine, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
  • 2 Massachusetts General Hospital, Department of Surgery, Boston, MA, USA; Massachusetts General Hospital, Division of Cardiovascular Surgery, Boston, MA, USA.
  • 3 Massachusetts General Hospital, Department of Surgery, Boston, MA, USA; Massachusetts General Hospital, Division of Surgical Oncology, Boston, MA, USA.
  • 4 Duke University Medical Center, Department of General Surgery, USA.
  • 5 Massachusetts General Hospital, Center for Regenerative Medicine, Boston, MA, USA.
  • 6 Massachusetts General Hospital, Center for Regenerative Medicine, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital, Department of Pathology, Boston, MA, USA.
  • 7 Massachusetts General Hospital, Center for Regenerative Medicine, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital, Department of Surgery, Boston, MA, USA. Electronic address: hott@mgh.harvard.edu.
PMID: 35533440 DOI: 10.1016/j.biomaterials.2022.121509
Abstract

The catastrophic global effects of the SARS-CoV-2 pandemic highlight the need to develop novel therapeutics strategies to prevent and treat viral infections of the respiratory tract. To enable this work, we need scalable, affordable, and physiologically relevant models of the human lung, the primary organ involved in the pathogenesis of COVID-19. To date, most COVID-19 in vitro models rely on platforms such as cell lines and organoids. While 2D and 3D models have provided important insights, human distal lung models that can model epithelial viral uptake have yet to be established. We hypothesized that by leveraging techniques of whole organ engineering and directed differentiation of induced pluripotent stem cells (iPSC) we could model human distal lung epithelium, examine viral Infection at the tissue level in real time, and establish a platform for COVID-19 related research ex vivo. In the present study, we used type 2 alveolar epithelial cells (AT2) derived from human iPSCs to repopulate whole rat lung acellular scaffolds and maintained them in extended biomimetic organ culture for 30 days to induce the maturation of distal lung epithelium. We observed emergence of a mixed type 1 and type 2 alveolar epithelial phenotype during tissue formation. When exposing our system to a pseudotyped lentivirus containing the spike of wildtype SARS-CoV-2 and the more virulent D614G, we observed progression of the Infection in real time. We then found that the Protease inhibitor Camostat Mesyalte significantly reduced viral transfection in distal lung epithelium. In summary, our data show that a mature human distal lung epithelium can serve as a novel moderate throughput research platform to examine viral Infection and to evaluate novel therapeutics ex vivo.

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