Revolutionary Human Cell Culture Model for Studying Lung Immune Function

Alveolar macrophages reside deep within the lungs, where they play a vital role in clearing out bacteria, viruses, and other harmful invaders. Traditionally, isolating these specialized cells from donors to study them has been invasive, costly, and labor-intensive. Researchers at Texas Biomedical Research Institute (Texas Biomed) have created a groundbreaking method to generate human “alveolar macrophage-like (AML)” cells in the laboratory, which closely resemble these important macrophages. They documented their findings on AMLs in the previous year.

This model is already benefiting global biomedical research efforts.

In the recent Nature study, AML cells were employed alongside various other cell-based models and comprehensive genetic studies involving humans to reveal new information about an immune-signaling protein known as tumor necrosis factor (TNF) and its involvement in tuberculosis (TB). This collaborative international effort was spearheaded by a team from The Rockefeller University in New York, the Laboratory of Human Genetics of Infectious Diseases in Paris, France, and the University of Antioquia UdeA in Medellín, Colombia.

“It’s thrilling to see scientists across the globe utilizing the AML model in their research, uncovering the fundamental mechanisms of the immune system that may alter our approach to treating infectious diseases,” stated Larry Schlesinger, M.D., Texas Biomed Professor and President/CEO, who co-developed the AML model with Staff Scientist Susanta Pahari, Ph.D.

Crucial Experiments

Historically, TNF has been regarded as crucial for safeguarding humans and many other species from infections. The study revealed that while TNF is indeed vital for protection against TB, it does not play the same role for all infectious diseases. This conclusion arises from thorough genetic studies of two cousins from Colombia, who lack functional TNF yet have lived into their 20s and 30s while experiencing recurrent TB, remaining otherwise healthy without other significant illnesses.

Research using the AML model and other cell models clarified the mechanisms involved. Specifically, TNF initiates the production of molecules referred to as reactive oxygen species (ROS) within alveolar macrophages, which are critical for destroying Mycobacterium tuberculosis, the bacteria responsible for TB. When TNF is absent or inhibited, the release of ROS is blocked, allowing the bacteria to proliferate within the lungs.

An accompanying article titled “News and Views” in Nature commented that this project signifies a thorough blend of clinical and functional research, opening up new questions for exploration.

For instance, it raises the possibility that functions previously assigned to TNF might actually be performed by other molecules, suggesting new potential targets for treatment of inflammatory disorders, according to a press release from Rockefeller.

“As researchers, our goal is to make new discoveries, but equally fulfilling is the creation of tools that empower others to achieve their breakthroughs and have a wider impact on public health,” expressed Dr. Pahari.

Advantages of the AML Model

Traditionally, researchers had to collect alveolar macrophages from donors through invasive and costly lung wash procedures. Previous macrophage models lacked certain distinctive features specific to alveolar macrophages. The AML model effectively resolves both of these challenges by starting with a simple blood draw from donors. Blood monocytes, which are a type of immune cell, are combined with substances that replicate the lung environment in a cell culture dish. Within a week, the monocytes develop into cells very similar to alveolar macrophages, suitable for studies such as this one. Presently, these AML cells are being tested in more complex lung-on-chip models, with specialized ingredients being assessed for generating even larger numbers of AMLs from stem cells.