Stem cell-derived human lung organoid model- the next chapter in Viral Disease Research?

Sampriti Roy, Asutosh College, University of Calcutta

SARS-CoV-2, the talk of the town (read “world”), still lacks information related to its origin and exact mechanism.  The virus, found to cause DAD (diffuse alveolar damage), leads to respiratory failure which appears to be the common mechanism of death in patients with severe COVID-19 infection. However, with lack of clarity persisting in the infection mechanisms, the challenge now posed before researchers are to understand the out-of-control immune reaction to the SARS-CoV-2 infection (cytokine storm).

Some of the models such as 3D airway models from iPSCs or tissue-resident cells, 3D organoids from bronchospheres and tracheospheres, air-liquid interface (most common drug-screening model), etc. have been seen in the field of COVID-19 modelling. However, these organoids virtually failed to express any lung mesenchyme or alveolar signature.

However, a recent study by Courtney Tindle et al. claims to present a personalized, propagable and cost-effective stem cell-derived human lung organoid model that consists of both proximal and distal airway epithelia.  In the model, monolayers that were derived from ALOs (adult lung organoids) were found to best recapitulate the transcriptomic signatures in diverse cohorts of COVID-19 patients’ respiratory samples. The ALO monolayers, when mixed with proximodistal airway components, recapitulated both proximal and distal cells.

Discovery:

The most important discovery claimed to have been made by the authors is the creation of adult lung organoid with both distal and proximal alveolar epithelia- which can not only be stably propagated in 3D cultures but also can be used as monolayers of mixed cellularity for modelling viral and host immune responses.  

When objectively analysed against patient-lung derived transcriptomes, the model containing both distal and proximal alveolar signatures was found to have a clear advantage over ones that contained only one of the alveolar signatures.

Some of the key features, as presented by the authors, are as follows:

• The modelling of a human lung organoid, complete with distal and proximal signatures has not been accomplished before theirs.
• Evidence regarding the retaining of the distal and proximal cellularity is given.
• 4 key features kept in mind while developing the lung models:

1. Reproducibility
2. Personalization
3. Modularity
4. Cost-effectiveness

• Protocols for generating lung organoids that could be reproduced in both genders and regardless of the donor’s smoking status, growth characteristics and consistency in outcome were observed across all isolation attempts.
• Value of the ALO models is further enhanced due to the availability of companion readouts/ biomarkers (e.g., ViP signatures, etc.) that can rapidly vet treatment efficacy based on set therapeutic goals.

The recent gap observed between COVID-19 in humans and animals presents the need for models like the one in the discussion, in conjunction with ViP signatures, that could serve as a pre-clinical model with companion diagnostics to identify drugs that target both viral and host response in pandemics.

In conclusion, the findings validate a human lung model of COVID-19 that can efficiently be used to investigate COVID-19 pathogenesis and even be used to vet new vaccines and therapies.

Also read: A new strategy for Covid: Targeting TMPRSS2 and ACE2 (Androgenic Regulations)

Source: DOI:  https://doi.org/10.1101/2020.10.17.344002

https://www.biorxiv.org/content/10.1101/2020.10.17.344002v2.full.pdf

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