If laminin were a superhero, it would most likely be Superman. As a major component of cells’ scaffolding, laminin may not be flashy or wear a red cape, but the marshmallow twist-shaped protein has the same regenerative power as the fictitious but all powerful man of steel.
Laminins use their three chains of amino acids to form different versions of themselves depending on the environment. Fascinated by these versatile proteins, Professor Karl Tryggvason from Duke-NUS has dedicated much of his career to investigating laminins’ superpowers.
“Over the last ten years, my research group has demonstrated the potential of using laminins, the evolutionarily oldest matrix protein, in regenerative medicine,” said Tryggvason.
And like the DC superhero, this family of proteins, which Tryggvason and his team established influence stem cell differentiation, holds the key to countless regenerative therapies—for damaged hearts, sightless eyes and even severe skin burns.
“Using highly cell-type-specific laminins, we have been successful in developing fully humanised, chemically defined, highly reproducible and non-tumorigenic differentiation protocols for making several cell types derived from human embryonic stem cells for use in regenerative medicine for several prevalent human diseases,” added Tryggvason.
Fixing a broken heart
Heart disease was responsible for almost one in three deaths in Singapore in 2020. Yet many more people live with diseased hearts that no longer pump blood fast enough around the body or with heart muscles scarred stiff from a heart attack. For them, the hope of a full recovery is usually slim.
Recognising the need to provide heart patients with more treatment options, Tryggvason collaborated with scientists around the world to engineer an approach to regenerate heart muscle cells using laminin-221, a version of the superhero protein that is abundantly present in heart muscles and human embryonic stem cells.
In preclinical experiments, laminin-221-induced heart muscle stem cells were injected into damaged hearts where they developed from stem cells into new heart muscle cells. Using this approach, the team managed to increase heart function from 60 per cent to 80 per cent, and maintain it at this level for 12 weeks. The team further confirmed their observations, demonstrating that their technique could work on damaged hearts of similar size and function to human hearts.
“Our technique has shown to be safe and effective by regenerating the damaged heart muscle and improving heart function. We are in the process of translating our technology into cellular therapeutic products,” said Dr Lynn Yap from Tryggvason’s team, who is spearheading this study.
“Finding ways to help patients improve their quality of life and wellbeing has always been the goal of my research. Finally, we have a product that can repair damaged hearts and help patients with heart failure live longer and better. I am definitely very excited,” added Yap who is a Principal Research Scientist at the Duke-NUS’ Cardiovascular and Metabolic Disorders Programme.
Tryggvason and his team are hoping to start Phase One clinical trials in two to three years’ time.
“Our technique could provide a path forward in the area of cardiovascular therapy. The development of clinical-quality progenitor cells for regenerative cardiology in humans can create an impact in patients’ lives,” said Tryggvason, who is also the Tanoto Foundation Professor in Diabetes Research.
Treating retinal disorders
Tapping the effects that different types of laminins exert on stem cells, Assistant Professor Tay Hwee Goon from Tryggvason’s team developed a method using this versatile protein to help restore the sight of visually challenged people.
Her method makes use of laminins to generate photoreceptor progenitor cells from human stem cells. Photoreceptors convert light into signals that the brain can decode into images. They are also crucial in seeing colours and in the dark.
Our strategy is to transplant these photoreceptor progenitors, which still have the capability to regenerate and repair in the host retina’s environment. We found that the engrafted cells inhibit further host retina deterioration and improved visual function in preclinical studies, based on the electroretinogram analysis,” said Tay who is also with Duke-NUS’ Cardiovascular and Metabolic Disorders Programme.
The team has obtained promising results from initial studies and is conducting further research to validate the findings. If results remain promising, the team hopes to move into human trials.
“Our patented method could advance to clinical use, where it has the potential to restore sight of visually challenged patients, alleviating the burdens and inconveniences that come with the loss of vision,” said Tryggvason.
“The opportunity to translate my research interest to bedside practice has strongly motivated me to work on developing this idea into a functional retinal product and potentially turning it into a therapeutic reality to improve human lives,” added Tay.
Skin cell sheets for treating burn patients
At the Singapore General Hospital (SGH) Burn Centre, laminins’ superpower has been harnessed since 2018 when Tryggvason along with SGH Assistant Director of Transplant Research Dr Alvin Chua developed a safer and more efficient method for growing human skin for grafting onto burn patients’ wounds. It was the first time that recombinant laminins were used to grow human skin sheets in the lab.
“For more than four decades, skin cells have been cultivated using a combined human-animal culture system. From a clinical application standpoint, this approach exposes patients to the potential risk of zoonotic infections and adverse immune reactions,” said Chua, who co-led the study.
“Our technique uses biologically relevant and human-based laminin proteins—LN-511 or LN-421—as a substitute for mouse cells to grow human skin epithelial cells. The preparation of these laminin proteins involves only a simple coating procedure applied overnight, whereas the conventional method takes between five to seven days. Therefore, on top of being safer, our laminin-based cell culture system also improves productivity with reduction in manpower and manufacturing time, facilitating the expedited delivery of cell sheets to patients who need them urgently,” added Chua.
In preclinical tests, the team has been able to grow new skin as effectively as with the existing method. The team is now in the process of preparing for a Phase One clinical trial to test the method’s effectiveness on humans.
“Our method of using laminins in their pure forms to develop a fully human cell culture system for growing skin epithelial cells in the laboratory is a first and is likely to translate into novel treatments for many different skin disorders and wounds,” said Tryggvason.
Laminins, like Clark Kent, have a special side to them, one that makes them ideal candidates to be used in all kinds of regenerative medicine. And Tryggvason is determined to unlock the full superhero potential by uncovering the mysteries behind this family of mighty proteins: “I foresee that laminins can play an important role in the development of robust methodologies that can impact the advancement of regenerative medicine.”