How Organoids Provide a Model System for Intestinal Regeneration and Repair

Caroline Lindemans, M.D., Ph.D., Clinician Scientist, University Medical Center
Caroline Lindemans, MD, PhD

Dr. Lindemans earned both her MD and PhD from the University Of Utrecht, the Netherlands. She is currently a Clinical Scientist at the University Medical Center Utrecht and a Research Fellow in the lab of Dr. Marcel van den Brink at the Memorial Sloan Kettering Cancer Center. Her work centers around pediatric bone marrow transplantation, specializing in investigation of graft-vs.-host disease and potential therapies for this disease.


The Scientist

What inspired you to pursue scientific research?

The clinical needs of patients is my primary motivation, and for the last 10 years this has included patients undergoing allogeneic hematological transplantation. The field is developing at a fast pace, however, there is still room to improve outcomes, both by reducing toxicity and increasing affectivity. There are many examples of developments that were the result of asking the right questions and applying the newest available techniques basic research has to offer.


Do you have a scientific idol that influenced the scientific path you’ve chosen?

I’ve been inspired by many scientists from near and far. A good example is Professor Hans Clevers (Hubrecht Institute, Utrecht) who developed the powerful new organoid model and tissue culture systems in which both normal tissues and tumor material can be investigated. As well, clinical scientists such as Professor Marcel van den Brink (Memorial Sloan Kettering Cancer Center, NYC) have inspired me to apply basic research to investigate relevant clinical questions, and stay involved in clinical care for patients. It is a busy life, but much is possible if you want it to happen.


What led you to studies in your current field?

Intestinal graft-versus-host disease is a severe complication of transplantation with donor hematopoietic cells. It is striking how long these patients take to recover, and how poor their prognosis is. I have always been interested in the intricate interactions between target tissues such as the gut and the immune system.


What hobbies do you have outside of the lab?

I have two adorable little girls that amaze me and keep my days more than occupied. Outside of a busy family life, I love to travel, have a passion for singing, and enjoy live music as much as possible.


The Science

Please describe the focus of your current research

We study the interactions between epithelium and immune cells, and investigate how the immune system is involved in both causing damage and recovery from damage.


What do you consider to be the most important advance(s) in intestinal research in the last five years?

Personally, I believe that our understanding of intestinal crypt regeneration, and the factors that are involved, is one of the most important advances in this field.


What breakthroughs would you anticipate in the next five years?

High throughput chemotherapeutic testing of tumor organoids and identification of novel drugs will certainly move the field forward. Therapeutic transplantation of organoids for certain tissues, such as the liver, may turn out to be feasible.


What has the adoption of organoid cultures added to your research? What types of biological questions has this technique enabled you to probe?

Organoid culture has enabled us to examine the specific and direct effects of IL-22 on intestinal regeneration which is not tractable using animal models. Using intestinal organoids from the tissue of genetically modified mice with a reporter gene for a certain cell type, we were able to investigate the effects of Il-22 on specific intestinal crypt cell types. As such, we discovered that intestinal stem cells, and not the Paneth cells, are the targets leading to the increased regeneration response of IL-22 after damage.


What impact do you see organoids having on the intestinal field? What technical hurdles remain before this can be realised?

The organoid culture system is currently being investigated to determine the possibility of organoid transplantation for patients with genetic epithelial defects. One could imagine transplanting donor organoids, or organoids genetically corrected with CRISPR/Cas9 methodologies. However, although the proof-of-principle was shown in mice using the large intestine, it has been quite difficult to do the same for small intestine. So far, studies have shown that a large percentage of the intestine requires engraftment before it will lead to symptomatic correction in these patients, and this may remain a major challenge.


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