Transforming organ transplantation with regenerative medicine: an interview with Giuseppe Orlando

Could you provide an overview of your current research in cell therapy in relation to the kidney & pancreas?

We are currently working on different projects. In the case of the kidney, we are trying to understand the pathways that orchestrate adaptive repair after damage to the organ. From this, we are looking to develop strategies to facilitate organ repair after damage, with the goal of rendering transplantable organs that would otherwise be untransplantable. To achieve this, we are testing both cells and cell organelles like mitochondria, and so far, the results have been encouraging.

Looking at the pancreas and beta cell replacement, we have been using extracellular matrix-based biomaterials derived from the mammalian pancreas to improve islet performance post-transplantation. The rationale behind using these naturally derived biomaterials is that they could enhance the survival and performance of the islets over an extended period. We are also testing whether 3D printing technology may help manufacturing islet-based constructs on a large scale.

What are some of the current applications of regenerative medicine in organ transplantation?

For more than a century, regenerative medicine concepts have been incorporated into organ transplantation. Just think about the field of organ preservation, which de facto means ‘repairing’ or ‘regenerating’ organs, a fundamental concept in regenerative medicine. Now, it's expanding with the convergence of transplant medicine and regenerative medicine becoming a common occurrence. If we want to do a futile exercise of semantics, let's focus on the term ‘cell therapy’, another keystone of regenerative medicine. Well, when we transplant an organ, we implant a massive multicellular system. Shall we then consider transplantation synonymous with regenerative medicine?

In the field of beta cell replacement, we are seeing the bioengineering of progenitor cells toward phenotypes that are insulin-dependent and islet-like, to treat Type 1 diabetes. As trials continue to progress, we are advancing toward the clinical translation of this therapy. It is likely that this approach could also be utilized for Type 2 diabetes. Other examples include mitochondrial transplants and the use of stem cells and extracellular vesicles to repair organs.

What are some of the key advancements in regenerative medicine that have significantly impacted organ transplantation?

Stem cell engineering and the use of extracellular matrix-based biomaterials to improve added function has had a significant impact on the field. We have also seen improvements in organ preservation utilizing regenerative medicine concepts. In recent years, 3D bioprinting has been utilized to bioengineer organs. The use of decellularization and recellularization technology could be used to build and manufacture organs for transplant purposes. Last, blastocyst complementation is a cutting-edge field of organ engineering science where many new technologies like gene editing, xenotransplant, stem cell engineering, merge.

How do you see regenerative medicine shaping the future of transplantation?

The history of transplant medicine can be summarized in three phases. The first was the surgical era, where somebody had the intuition that a terminally diseased organ could be replaced with a new functioning organ. In those days, success was not the usual outcome because we could not leverage on potent and effective immunosuppressants. The advent of cyclosporine changed everything.

Following this, we transitioned into the second phase, which could be labeled as the immunology or immunosuppressive era that started in the 1970s. This phase is ending because we are now transitioning to the third phase which is the regenerative medicine era. This may not be obvious to the majority of the members of the transplant community, who are not familiar with progress occurring in regenerative medicine. But it is clear to me.

Now, what was initially an immunology-based discipline is now becoming a regenerative medicine-based discipline.

In comparison to other fields, transplant medicine has a growing interest in accelerating and fostering the advancements of regenerative medicine. The trajectory of the field will be determined by the progression of regenerative medicine.

What are some of the most promising areas of future research in regenerative medicine & organ transplantation?

We need to develop strategies to identify potential inexhaustible sources of organs, for example through 3D printing, organ decellularization-recellularization, interspecies blastocyst complementation and stem cell engineering.

The possibility of inducing in vivo organ regeneration following a transplant could be significant for both fields. This avenue of research could potentially ensure the functionality and longevity of the transplanted organ over several decades.

In summary, there are many exciting things to come, mainly in organ engineering.