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Mini-Lungs in a Lab Dish Mimic Early COVID-19 Infection

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Credit: Arvind Konkimalla, Tata Lab, Duke University, Durham, NC

Researchers have become skilled at growing an array of miniature human organs in the lab. Such lab-grown “organoids” have been put to work to better understand diabetes, fatty liver disease, color vision, and much more. Now, NIH-funded researchers have applied this remarkable lab tool to produce mini-lungs to study SARS-CoV-2, the coronavirus that causes COVID-19.

The intriguing bubble-like structures (red/clear) in the mini-lung pictured above represent developing alveoli, the tiny air sacs in our lungs, where COVID-19 infections often begin. In this organoid, the air sacs consist of many thousands of cells, all of which arose from a single adult stem cell isolated from tissues found deep within healthy human lungs. When carefully nurtured in lab dishes, those so-called alveolar epithelial type-2 cells (AT2s) begin to multiply. As they grow, they spontaneously assemble into structures that closely resemble alveoli.

A team led by Purushothama Rao Tata, Duke University School of Medicine, Durham, NC, developed these mini-lungs in a quest to understand how adult stem cells help to regenerate damaged tissue in the deepest recesses of the lungs, where SARS-CoV-2 attacks. In earlier studies, the researchers had shown it was possible for these cells to produce miniature alveoli. But there was a problem: the “soup” they used to nurture the growing cells included ingredients that weren’t well defined, making it hard to characterize the experiments fully.

In the study, now reported in Cell Stem Cell, the researchers found a way to simplify and define that brew. For the first time, they could produce mini-lungs consisting only of human lung cells. By growing them in large numbers in the lab, they can now learn more about SARS-CoV-2 infection and look for new ways to prevent or treat it.

Tata and his collaborators at the University of North Carolina, Chapel Hill, have already confirmed that SARS-CoV-2 infects the mini-lungs via the critical ACE2 receptor, just as the virus is known to do in the lungs of an infected person.

Interestingly, the cells also produce cytokines, inflammatory molecules that have been tied to tissue damage. The findings suggest the cytokine signals may come from the lungs themselves, even before immune cells arrive on the scene.

The heavily infected lung cells eventually self-destruct and die. In an unexpected turn of events, they even induce cell death in some neighboring healthy cells that are not infected. The relevance of the studies to the clinic was boosted by the finding that the gene activity patterns in the mini-lungs are a close match to those found in samples taken from six patients with severe COVID-19.

Now that he’s got the recipe down, Tata is busy making organoids and helping to model COVID-19 infections, with the hope of identifying and testing promising new treatments. It’s clear these mini-lungs are breathing some added life into the basic study of COVID-19.

Reference:

[1] Human lung stem cell-based alveolospheres provide insights into SARS-CoV-2-mediated interferon responses and pneumocyte dysfunction. Katsura H, Sontake V, Tata A, Kobayashi Y, Edwards CE, Heaton BE, Konkimalla A, Asakura T, Mikami Y, Fritch EJ, Lee PJ, Heaton NS, Boucher RC, Randell SH, Baric RS, Tata PR. Cell Stem Cell. 2020 Oct 21:S1934-5909(20)30499-9.

Links:

Coronavirus (COVID-19) (NIH)

Tata Lab (Duke University School of Medicine, Durham, NC)

NIH Support: National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences; National Institute of Diabetes and Digestive and Kidney Diseases

4 Comments

  • Carol Howarth says:

    It’s great that medics are working on areas that may benefit Covid19 and hopefully a cure will soon be reached for everyone and an antidote jab for prevention of the disease.

  • Judy says:

    Maybe after solving Covid you could try regrowing kidneys

  • DR. SAUMYA PANDEY, PH.D. says:

    Amazing mini-lungs organoid model study for demystifying SARS-Covid19 susceptibility in genetically distinct populations; future pharmacogenetic clinical research collaborative endeavors are warranted for eventual long-term patient-friendly public health research models in lung physiology translational research area.
    Dr. Saumya Pandey, Ph.D., congratulates Dr. Francis Collins, MD-PHD, for this expert opinion biomedical research snapshot!
    Could the enigmatic Toll-like Receptors and/or Wnt-Receptors prove to be the potential “missing link” in the eventual “Covid-19-mini-lungs benchside to bed” endgame?

  • Bruce J McCaig says:

    I found a possible host for a universal immunity to all coronaviruses and flesh eating bacteria. Birds only have a rudimentary endocrine system. By and large they rely on the bacterial populations in their intestines to provide immunity to parasitic bacteria that enter them through dietary changes. The symbiotic relationship, established over millennia, is transferred from parent to offspring, over time, the bacteria are exposed to new viral and bacterial parasites, the host super colonies share modifications to their dna via the transfer of transposons and episomes while the confront the new invading parasitic organism. The coronaviruses and flesh eating bacteria have one common variable, the cellular membranes on all these parasites are composed of phospholipids (to be metabolized for energy) and glycoproteins to form the outer cellular membrane. The phospholipids gravitate to the membrane during the replication process. Once a symbiotic bacterial population determines an immune factor that neutralizes the invader the informational packets via the transposons and episomes are transferred to the super colony. The pigeon populations in most cities throughout the world are of the family Columbiae, they will be carriers of the covid 19, and spread the virus via their droppings in common water sources such as fountains or AC outlets. It is possible that these birds could be used in a biological attack. They will quickly even in small numbers infect the host population. For example NYC has a HOST POPULATION OF 7 MILLION STRONG. The Mourning Dove is in the same family as the common city pigeon, the variable factors within the Dove population is possible bacterial genomes are all alkaline based in nature, this factors into the presence of a universal immunity, in addition the doves lifespan is measured in decades versus the pigeons years. The wild dove population number 425 million in the U.S.A. alone this increases the odds considerably that they have acquired a herd immunity to these acid bases organisms. Since our human large intestines are completely populated by the same plant based alkaline bacteria, we can be inoculated with the herd immunity the doves have already without any deleterious effects to our host super colony. We simply sample and culture the doves colonies, include in the culture medium, the alkaline glycine buffer solution, or endothelial lipase our bodies utilize to hydrolyze mucus (composed of phospholipids) do you see the parallel relationship we share with birds, are immune systems are by and large dependent on the super colonies of the large intestines to provide the building blocks the bone marrow needs for our immune system. The birds have hollow bones, so they rely totally on the bacteria within them for their immune system, the lower you go in species development the task of the immune system is solely dependent on the symbiotic relationship between the host and bacteria. We may be able to take advantage of this universal standard within species development to create probiotic solutions to infections that occur within the human population worldwide. I believe with the current crisis we now face, this may be a quick and dirty solution. We sample the doves, and other wild bird species, culture their super colonies in total, and expose the colonies to the coronavirus. I think you will be surprised to find that Mother Nature has included that common adaptation within all the wild birds and will allow the inclusion of human kind with that cross species herd immunity. PEACE AND GOOD WILL

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