Healthcare (Commonwealth Union) – Crohn‘s disease, an autoimmune condition, causes chronic inflammation of the digestive tract, leading to a range of severe gastrointestinal symptoms that vary widely among individuals. The disease can severely damage the gut lining, often necessitating multiple surgeries. Despite ongoing research, Crohn’s remains poorly understood, with no cure and limited treatment options. The complexity of the disease, compounded by its variability across patients, has made developing effective therapeutics challenging. A significant hurdle has been the absence of preclinical animal models that faithfully mimic the disease, as well as the diverse nature of the condition in patients, complicating personalized treatment approaches.
Previous research has used organoids derived from pluripotent stem cells programmed to develop into gut cells to study Crohn’s disease. However, researchers at the University of California San Diego have now focused on organoids grown from adult stem cells sourced from the gut tissue of Crohn’s patients, which better reflect the disease’s characteristics. This approach led to the discovery that Crohn’s disease has two distinct molecular subtypes.
These findings, which appeared last month, in Cell Reports Medicine, could pave the way for more accurate diagnostics and personalized treatments tailored to each subtype.
The research team collected gut tissue samples from 53 Crohn’s disease patients during routine colonoscopies at UC San Diego Health’s Inflammatory Bowel Disease Center. These patients represented a diverse group, exhibiting various clinical symptoms. Led by Courtney Tindle, director of the UC San Diego HUMANOID™ Center of Research Excellence, the scientists created a “biobank” of patient-derived organoid cultures.
Organoids are miniature, lab-grown versions of organs or tissues that closely mimic the functions of their real counterparts, making them valuable for studying diseases when animal models fall short.
Prior research that focused on Crohn’s disease have derived organoids from pluripotent stem cells. However, the formation of the organoids from adult stem cells in gut tissue more precisely replicates the traits of the disease, as indicated by the senior author Pradipta Ghosh, M.D., professor of cellular and molecular medicine as well as executive director of the HUMANOIDTM Center.
“The pluripotent stem cells — whether derived from blood or skin cells, carry the genetic traits of the patient, but have no way to know the inflamed environment inside the patient’s gut,” explained Ghosh. In contrast, adult stem cells preserve an epigenetic memory of the gut atmosphere imprinted on their genetic makeup, reflecting the previous exposure to bacterial colonization, inflammation, as well as changes in oxygen and pH levels. “We show here that adult stem cell-derived organoids accurately mimic the inflamed gut, but the pluripotent cells fail, which reminds me of what Maya Angelou once said: ‘I have great respect for the past. If you don’t know where you’ve come from, you don’t know where you’re going,’” she continued.
When the researchers analyzed the data, they were surprised to find that, despite recruiting patients with a wide range of clinical symptoms, the organoids consistently fit into just two distinct molecular subtypes. Each subtype displayed unique patterns of genetic mutations, gene expression, and cellular characteristics.
Immune-deficient infectious Crohn’s disease (IDICD): This subtype is marked by an inability to effectively eliminate pathogens and a weakened cytokine response from the immune system. Patients with this form often develop fistulas with pus discharge.
Stress and senescence-induced fibrostenotic Crohn’s disease (S2FCD): This subtype is characterized by cellular stress and aging, leading to fibrosis, or scarring, of the gut’s epithelial tissue, which can result in the formation of strictures.
Ghosh believes the identification of these two distinct molecular subtypes could revolutionize the traditional understanding of Crohn’s disease. Rather than categorizing patients based on a wide array of clinical symptoms, grouping them by their specific molecular subtype could pave the way for more personalized and effective treatment strategies.
Healthcare (Commonwealth Union) – Crohn‘s disease, an autoimmune condition, causes chronic inflammation of the digestive tract, leading to a range of severe gastrointestinal symptoms that vary widely among individuals. The disease can severely damage the gut lining, often necessitating multiple surgeries. Despite ongoing research, Crohn’s remains poorly understood, with no cure and limited treatment options. The complexity of the disease, compounded by its variability across patients, has made developing effective therapeutics challenging. A significant hurdle has been the absence of preclinical animal models that faithfully mimic the disease, as well as the diverse nature of the condition in patients, complicating personalized treatment approaches.
Previous research has used organoids derived from pluripotent stem cells programmed to develop into gut cells to study Crohn’s disease. However, researchers at the University of California San Diego have now focused on organoids grown from adult stem cells sourced from the gut tissue of Crohn’s patients, which better reflect the disease’s characteristics. This approach led to the discovery that Crohn’s disease has two distinct molecular subtypes.
These findings, which appeared last month, in Cell Reports Medicine, could pave the way for more accurate diagnostics and personalized treatments tailored to each subtype.
The research team collected gut tissue samples from 53 Crohn’s disease patients during routine colonoscopies at UC San Diego Health’s Inflammatory Bowel Disease Center. These patients represented a diverse group, exhibiting various clinical symptoms. Led by Courtney Tindle, director of the UC San Diego HUMANOID™ Center of Research Excellence, the scientists created a “biobank” of patient-derived organoid cultures.
Organoids are miniature, lab-grown versions of organs or tissues that closely mimic the functions of their real counterparts, making them valuable for studying diseases when animal models fall short.
Prior research that focused on Crohn’s disease have derived organoids from pluripotent stem cells. However, the formation of the organoids from adult stem cells in gut tissue more precisely replicates the traits of the disease, as indicated by the senior author Pradipta Ghosh, M.D., professor of cellular and molecular medicine as well as executive director of the HUMANOIDTM Center.
“The pluripotent stem cells — whether derived from blood or skin cells, carry the genetic traits of the patient, but have no way to know the inflamed environment inside the patient’s gut,” explained Ghosh. In contrast, adult stem cells preserve an epigenetic memory of the gut atmosphere imprinted on their genetic makeup, reflecting the previous exposure to bacterial colonization, inflammation, as well as changes in oxygen and pH levels. “We show here that adult stem cell-derived organoids accurately mimic the inflamed gut, but the pluripotent cells fail, which reminds me of what Maya Angelou once said: ‘I have great respect for the past. If you don’t know where you’ve come from, you don’t know where you’re going,’” she continued.
When the researchers analyzed the data, they were surprised to find that, despite recruiting patients with a wide range of clinical symptoms, the organoids consistently fit into just two distinct molecular subtypes. Each subtype displayed unique patterns of genetic mutations, gene expression, and cellular characteristics.
Immune-deficient infectious Crohn’s disease (IDICD): This subtype is marked by an inability to effectively eliminate pathogens and a weakened cytokine response from the immune system. Patients with this form often develop fistulas with pus discharge.
Stress and senescence-induced fibrostenotic Crohn’s disease (S2FCD): This subtype is characterized by cellular stress and aging, leading to fibrosis, or scarring, of the gut’s epithelial tissue, which can result in the formation of strictures.
Ghosh believes the identification of these two distinct molecular subtypes could revolutionize the traditional understanding of Crohn’s disease. Rather than categorizing patients based on a wide array of clinical symptoms, grouping them by their specific molecular subtype could pave the way for more personalized and effective treatment strategies.
