Taking a Closer Look at Stem Cell Research: A Conversation with Francesca Mariani

Interview by Kimtee Kundu

https://doi.org/10.56927/277655

HHPR Senior Editor Kimtee Kundu interviewed Francesca Mariani, PhD. Dr. Mariani is an Associate Professor at the Keck School of Medicine of the University of Southern California (USC). She received her Ph.D. from the University of California, Berkeley and completed her Post-Doc at the University of California, San Francisco. Her expertise is in the area of stem cell biology, with particular focus on skeletal repair and regeneration. At the Keck School of Medicine, she currently runs a research lab and is the director of the Master's program in Stem Cell Biology and Regenerative Medicine. Dr. Mariani is also the co-director of a new program called COMPASS, which was funded by the California Institute for Regenerative Medicine (CIRM). COMPASS supports undergraduate students interested in getting involved in science. In addition, she teaches at the graduate level in the Ph.D. program, as well as in the medical school. Recently, she was recognized with the highest honor for outstanding teaching at USC, the 2023 Associates Award for Excellence in Teaching.

To ensure clarity, the interview below has been minimally edited.

Kimtee Kundu (KK): It is truly fascinating that you wear so many hats at USC! Among your other roles, you are a principal investigator for a stem cell research lab. What are you currently exploring with your laboratory team?

Dr. Francesca Mariani (FMD): Our lab, some years ago, developed one of the first models to study large scale repair in both cartilage and bone using a mammalian model system. We use this model to understand the cells and molecules that are involved in the repair process. We also explore ways to use this knowledge in developing new treatments for patients suffering from severe skeletal injuries.

KK: You mentioned investigating skeletal repair, so to follow up a bit more on that, what aspects of that is the lab currently working on?

FMD: We are currently determining the best way to engineer multiple stem cell types that can be used for stem cell-based bone repair therapies. This involves developing protocols to differentiate the cells into the skeletal cell types that we are looking for and ensuring that they behave as expected when those cell types are implanted into animal systems. We also want to make sure the cells are able to produce high quality skeletal tissue when implanted. Finally, we want to be able to track the cells, so that we know their location after implant, learn how long they remain at the repair site, and determine how long it takes for them to get remodeled out.

KK: Wow! It’s amazing that the Mariani Lab is working on this. Could you go more in depth on what has led you to focus on researching stem cells, and the potential it holds for regenerative medicine?

FMD: Yes, of course. Long ago, I came across some anecdotal reports showing that, while our skeleton can repair with a simple fracture, our skeleton typically doesn't repair very efficiently after a very large injury to the skeleton. However, an exception to this has been reported in some case studies. In humans, large injuries to the rib-cage can repair themselves quite well. This has been appreciated by cranio-facial surgeons, who will use a large segment of the bone from the rib to reconstruct the structures in the face.

A classic example is the use of rib segments in reconstructing a patient’s jaw. These cranio-facial surgeons have recognized that several months after they have taken this rib segment out, the patient’s ribs actually regenerated themselves. Amazingly, there are reports of between 6 to 8 inches of the cartilage or the bone portion of the rib cage regenerating after removal. This is quite a large region of tissue that regenerates itself!

Inspired by this observation in humans, we've developed a mouse model to examine this amazing phenomenon and to try to understand the cause of this large-scale regeneration. We're currently studying the exact properties of these cells. In addition, we've also discovered a critical growth factor that activates these cells and is absolutely required for this large scale repair. So, we're investigating the potential use of this growth factor in other contexts, such as large scale repair in other bones.

KK: This is all so captivating, and I’m amazed by the progress your research has made. It would be great to also know, what do you enjoy the most about your field of research, and are there any future outlooks that excite you?

FMD: There's a long history of using stem cells to treat various blood disorders, but the usage of stem cells for other types of disorders or diseases is still in infancy. One question I've been asked and I've thought a lot about is, what tissue or organ system in the human body might be the most amenable to stem cell therapy? It turns out that in comparison to other tissues, the skeleton is a relatively simple, yet important, tissue and may be one of the most amenable tissues to stem cell therapy. The skeleton supports and protects the rest of our body.

Cartilage consists of one main cell type, called a chondrocyte. Meanwhile, the bone is maintained with a few different cell types, including the main bone producing cell, called an osteoblast. Fortunately, these two cell types can be easily cultured in a petri dish. In addition, surgeons are already familiar with bone repair therapies that involve implanting special matrices into the injury site or even cells from the patient. So, using autologous cells from one part of the patient into another part of the patient to help cure bone injuries is already a common practice.

Considering all of that, developing stem cell-based therapies for bone repair is, I think, very exciting. I think it will have a relatively straightforward application of generating cells for integration within the bone, and that will make it fairly easy for surgeons to adopt the practice of using those same cells to repair injuries in patients.

KK: You mentioned developing stem cell based therapies and usage of findings by surgeons, which seems to be really promising! What are these new developments or applications in stem cell research that interests your lab?

FMD: Several exciting areas of research are on the horizon. I think it may be technically challenging to make stem cells from the patient directly with reliable quality control. An alternative on the horizon are universal donor stem cells. These are stem cells that can be human leukocyte antigen (HLA) type matched to the patient directly (to ensure that the patient’s HLC proteins enable the immune system to accept the cells) or are engineered to be non-immunogenic. The idea is that these cells can be used for stem cell therapy without the patient rejecting them. The second area that it's really exciting is that it's becoming more reliable and easier to edit the genome. It will, therefore, be possible to correct cells for a genetic mutation or to engineer cells that harbor important stem cell therapy genes.

For example, genes could be inserted that allow you to track the cells that you put in, or one could engineer the cells to be potentially eliminated in the future in the case they are no longer needed. The technology to generate these transgenic cell lines is just improving every day, and the process is becoming a lot easier and more accurate.

One of the challenges with stem cell therapy is that, depending on their use, the patient may need to be on immune rejection drugs for the rest of their lives. In addition, if the implanted stem cells are resident for the life of the patient, there may be a concern regarding the impact of having these cells that came from somewhere else, or that were genetically modified in their body forever. However, an amazing property about bone is that it constantly remodels itself constantly.

One interesting possibility is that stem cell therapies for bone repair could potentially be a short term type therapy. The cells could be put into place and their main role is to create a scaffold or bridge. This scaffold eventually could be remodeled and taken over by the patient's own cells. Therefore, the long term residence of the implanted cells may not be 100% necessary. That's a rather attractive idea because then a patient may only need to be on immune rejection drugs for a few years, instead of the rest of their life.

KK: There truly seems to be so much hope for the future with stem cell research and its applications within regenerative medicine. Thank you so much Dr. Mariani for sharing your contributions with us!