ASC Challenges: Expert Insights from Louis Casteilla

Hi Louis, thank you for being here today! To start off, given your experience with MSC-based therapies, how would you define MSCs and their role in regenerative medicine?

Louis: Thank you for having me! MSCs, or mesenchymal stem cells, are incredibly versatile. They’re the cells that give rise to mesenchymal tissues like bone, tendon, cartilage, and adipose tissue. When undifferentiated, they typically resemble fibroblasts and play a key role in producing the extracellular matrix, which provides structural support to tissues and aids in the proper functioning of specialized cells. They also display huge and versatile supportive paracrine activities. MSCs are crucial for tissue repair and stability, making them central to regenerative medicine.

That’s fascinating—thank you for breaking it down so clearly! Now that we have a better understanding of what MSCs are, could you tell us a bit more about how they’re being used in regenerative medicine today?

Louis: There are two main ways MSCs are applied in regenerative medicine. First, there’s the Direct Substitutive Effect, where MSCs are used to regenerate a tissue that’s damaged or missing. For example, if a bone is damaged, MSCs can be directed to become osteoblasts, the cells responsible for bone formation. Then, there’s the Supportive System approach. Here, MSCs aren’t necessarily replacing damaged cells directly. Instead, they play a role in creating a healing environment by influencing the surrounding tissue, even those tissues that aren’t mesenchymal. They do this through things like paracrine signaling, where they release factors that promote repair, or immunomodulation, which helps control inflammation and promotes healing. This way, MSCs help improve conditions for regeneration in various organs, supporting the body’s natural healing processes.

Are all MSCs the same, regardless of their origin?

Louis: Not exactly. MSCs were first identified in bone marrow, but now we know they’re present in many tissues, including adipose tissue, where they’re called ASCs. ASCs are the undifferentiated mesenchymal cells found in the stromal part of the adipose tissue and play the role of adipocyte progenitors. What’s interesting is that MSCs from different tissues can vary in their properties.

Can you give an example of those differences?

Louis: Sure. Adipose tissue has way more MSCs than bone marrow—about 100 times more per volume. So, from a therapeutic perspective, adipose tissue is much easier to work with because it’s simpler to collect, and you get way more cells with less expansion steps. Functionally, bone marrow MSCs are better for making bone, while ASCs are better for adipose tissue. Plus, ASCs tend to have stronger angiogenic properties—they’re excellent for promoting blood vessel formation—and they’re better at modulating inflammation and immune responses.

How do these differences impact therapeutic applications or production?

Louis:  From a production standpoint, adipose tissue is a huge advantage. Since you get so many MSCs from it, you don’t have to amplify the cells as much in the lab. That minimizes risks like cellular aging, genetic changes, or losing function during expansion, making the whole process safer and more efficient.

What types of diseases or injuries could be treated using ASCs?

Louis: The potential applications for ASCs are quite broad. For conditions affecting tissues like muscle or the heart, the focus is more on using ASCs to enhance the healing environment rather than directly transforming them into specialized cells. For instance, in heart diseases like myocardial infarction, ASCs won’t replace the damaged heart muscle cells directly. Instead, they play a crucial role in regenerating the tissue by promoting blood vessel growth and supporting recovery indirectly. In contrast, for bone injuries, ASCs can actively contribute to regenerating bone tissue, helping to restore function more directly.

So, it’s not just about adding the cells, but also about modifying the environment around them?

Louis: Exactly. When we regenerate an organ, we can either add cells directly or correct the environment, which helps the specialized cells function better. This is because the function of an organ relies on the interaction between these two populations of cells. If we impact one, we’re also affecting the other, which is why modifying the environment around the cells can be just as important as adding new cells to regenerate the tissue.

What are the most important characterization methods and quality control tests to ensure the safety and effectiveness of ASCs?

Louis: The key characterization tests focus on tumorigenicity, viability, and identity to ensure purity and consistency of the cells. After that, the quality control tests depend on the specific application. Unlike traditional drugs, quality control for ASCs must be multimodal because we can’t evaluate a living product with just one marker. This means we need multiple criteria to assess the product, and we must also be prepared for more variability than with chemical drugs. The challenge lies in balancing the necessary rigor with an acceptance of this natural variability.

That makes a lot of sense. With all of that in mind, how are ASCs actually used in clinical settings? Are they injected directly into patients, or do they require a specific preparation process before administration?

Louis: The classic process begins with the harvesting of fat, which can be performed via liposuction under local anesthesia which can be done by liposuction under local anesthesia. After that, the cells are dissociated, and this is where things are fairly simple. Essentially, we perform a cell sorting process based on simple adhesion and culture medium. The cells in suspension are placed in standard culture plates, where the cells can adhere to the surface with a specific medium. Under these conditions, the cells that don’t match the MSC type will not adhere. So, when we say we “seed the culture,” it’s essentially a selection step. Once that’s done, the cells multiply on a physical support. This support can be culture plates, flasks, or microbeads. However, at this stage, all culture processes are for adherent cells. We don’t yet know how to culture ASCs in suspension alone.

Thanks for that clear explanation! When it comes to MSC-based treatments, do you think it’s generally better to use autologous cells or allogeneic cells?

Louis: We’re moving from using autologous treatments, where the patient’s own cells are used, to allogeneic treatments, which involve donor cells. Autologous treatments are more expensive and time-consuming and there’s a delay between collecting the sample and administering the product, which means the patient has to survive that waiting period. Allogeneic treatments, on the other hand, offer advantages in terms of cost, time, and availability, but they bring the challenge of immune compatibility.

Although MSCs are considered immunoprivileged—meaning they are less likely to be recognized by the immune system—they are still detectable by immune cells in a different way compared to other cells. In allogeneic treatments, histocompatibility between the donor and recipient may not be as critical as with other types of cell therapies.

Since MSCs can be influenced by various factors, how does the quality of ASCs vary across different patients or contexts?

Louis: Yes, the quality of ASCs can vary depending on both the patient and the culture process. However, much of this variability can be reduced through the cell culture process, which helps to standardize the product. But despite this homogenization, some variability still exists, particularly due to epigenetic marks. These marks are influenced by the donor’s metabolic state, and factors like aging, obesity or diabetes can leave lasting effects.

That makes sense. Now, regarding cell communication, I’ve heard that exosomes produced by ASCs play a significant role. Can you explain what exosomes are and how they contribute to the therapeutic effects of ASCs?

Louis: Exosomes are tiny particles released by MSCs and ASCs during paracrine activity, carrying proteins, RNA, and receptors that communicate complex messages to their surroundings. However, they are just one aspect of cell signaling; cells also secrete other substances, like soluble molecules and extracellular matrix proteins, essential for tissue repair. While there’s speculation about exosomes replacing MSCs or ASCs in treatments, I believe that’s unlikely. Cells provide dynamic and adaptable responses to their environment, whereas exosomes are less flexible. Achieving the right exosomes requires the right cells and culture conditions, making it a more complex process than it seems.

But exosomes still have some advantages, right?

Louis: Yes, exosomes do have potential. Since they’re not whole cells, they could be safer and easier to manage in some ways. But they’re not a magic solution. They won’t answer all the questions, and they’re not necessarily simpler than using cells. It’s important to recognize that.

Where is the research on ASCs today? Are there any ongoing clinical trials or treatments available?

Louis: The research on ASCs has faced its share of disappointments, and it’s important to recognize that we may have moved too quickly in some areas. However, there are still promising developments to note. For instance, the treatment of graft-versus-host disease (GvHD) shows remarkable effectiveness with ASCs.

Currently, there are two approved ASC treatments, which vary by country, particularly for conditions like Crohn’s disease and GvHD. Moreover, researchers are exploring the potential of ASCs in other areas, such as ischemia and autoimmune diseases. While there are challenges ahead, the potential for ASC therapies remains significant, and I’m optimistic about what the future holds.

What challenges are researchers facing in advancing these treatments?

Louis: The main challenges include controlling the entire process, from cell collection to production, and ensuring consistent quality controls. ASCs are complex, and predicting their therapeutic effects is difficult. There’s also variability between treatment centers, which affects outcomes. Unlike chemical drugs, these treatments are not something you can take whenever you want and expect immediate effects. ASCs are much more complex, precise, and require tailored approaches. Educating healthcare providers on how to handle these therapies is crucial, and there’s still a lot of work needed to standardize and make these therapies widely accessible.

Have investors been discouraged by the slow progress?

Louis: Yes, there has been disappointment. Many have pulled out of the field because the results didn’t meet expectations in a short time. There was a misunderstanding about how ASCs work. Some results that were initially thought to be explained in one way turned out to be different. It’s a challenge because we’re dealing with living material, which is inherently variable and complex. This variability is compounded by the fact that we don’t fully understand these cells yet. So, it’s not as simple as with traditional drugs. It’s more of a dynamic medicine, which is a good thing, but also adds to the complexity.

What about the price issue?

Louis: Well, for me, the price issue is a transitional problem. The more interest there is, the more people get involved, and the lower the costs will become. The current costs are mainly due to the fact that these medications have arrived on the market with bioprocesses that were not fully optimized for the scale-up. But once a process is validated by regulatory agencies, it can’t be changed. This is where we might have tried to move too fast. There could have been optimization in the process that would allow these drugs to be delivered at a much lower price, far from what is currently being proposed.

So, are there any solutions for this?

Louis: This is part of Cell-Easy’s mission. There is a way to optimize things effectively and relatively quickly, if we approach it correctly. But, of course, it always takes time. The challenge is that investors and clinicians are under a lot of pressure to see clinical results. But ironically, this often leads to losing time, because if we rush into the clinic with a bioprocess that isn’t optimized, the economic model will likely be problematic in the long run.

What advice would you give to developers working on cell therapies, specifically those using ASCs?

Louis: My main advice is to have a clear vision from the very beginning of the steps that need to be taken to bring the therapy to market. Essentially, they need to think ahead and do what’s called “reverse engineering.” This means understanding the challenges that might arise and planning accordingly. For instance, using very rare products that are difficult to source under GMP conditions is not ideal. Even if the discovery is groundbreaking, it won’t necessarily lead to market success if these issues aren’t addressed early on.

What are some key elements developers should consider in this process?

Louis: Two critical elements are the bioprocess and the materials used. The approach and materials selected can make a big difference. Developers also need to assess the clinical efficacy early on, not just safety. This allows for the implementation of analyses in early clinical phases, ensuring that by Phase 3, the therapeutic potential is clear. Many people focus on how quickly they can get to market or how therapeutically effective they can be. But the real question is: How do you get to market efficiently, with a product that is not only therapeutically effective but also economically viable and profitable for the company? Sometimes the quickest way isn’t the most effective. It’s about balancing speed with long-term viability.

It’s also fundamental to surround yourself with the right multidisciplinary skills. You need biological expertise, medical knowledge, and engineering sciences. These areas of expertise must come together for a successful project.

Before we wrap up, is there anything else you’d like to share about the development of ASCs and their potential?

Louis: The development of ASCs has unfolded in three distinct phases. In the first phase, during the discovery period, there was a lot of excitement and optimism. We viewed ASCs and MSCs as almost miraculous, full of untapped potential for therapy. While there were some promising results, they didn’t quite live up to the grand expectations, which led to a period of disappointment and disillusionment. Today, we are still in the process of reassessing and refining our understanding. However, I am confident that, with ongoing research and progress, ASCs will eventually become a cornerstone of biotherapeutic treatments in the future.

Thank you so much for sharing your valuable insights today, Louis. This has been an enlightening discussion, and we look forward to seeing how ASCs evolve and contribute to the future of therapy.