Stem Cell Research & Therapy celebrates its fifth anniversary

To celebrate the fifth anniversary of our journal, Stem Cell Research & Therapy, I asked two editorial board members, Duncan J Stewart from the Ottawa Hospital Research Institute and Gianvito Martino from San Raffaele Hospital, about the advancements, challenges and future developments of research in this field.

What would you say has been the biggest advance in stem cell research and technology in the last five years?

Gianvito Martino (GM): The biggest advance in stem cell research in the last five years has been in the cell reprogramming field, a very rapidly growing field based on the seminal discovery that allows you to transform somatic cells into all types of cells indirectly – via induced pluripotent stem cells (iPS) – or directly.

While cell reprogramming is not a new discovery, and it secured the 2012 Nobel Prize to Shinya Yamanaka and John Gurdon, the new developments in this field have been very exciting.

The refinement and standardization of cell reprogramming’s protocols (direct or/and via iPS) have been carried out in several labs worldwide and major advances in the field include:

  1. The generation of human embryonic-like cells using the somatic cell nuclear transfer.
  2. The possibility to generate cerebral organoids from reprogrammed embryonic like cells that mimics the cellular organization of the developing human brain.
  3. The first ever transplant of iPS-derived retinal pigment epithelium in a patient suffering from age-related macular degeneration.

Duncan J Stewart (DJS): Reprogramming allows for the generation of autologous replacement cells for any organ of the body, potentially providing an unending supply of personalized tissue.

At the same time it rejuvenates host cells by virtue of the reprogramming, and thus overcomes one of the great limitations of the use of adult autologous cells, namely the deleterious effect of age and other consequences of disease on the regenerative activity of stem and progenitor cells.

However, despite the tremendous promise, it will likely be a number of years (or decades) before this technology could be widely applied in a safe and effective manner.

What are the main challenges we still face in terms of translating stem cell research into clinical practice and therapy?

GM: It is now evident that stem cells do not work exclusively through cell replacement but they can also promote, upon in vivo transplantation, tissue protection via the ‘bystander’ secretion of several types of molecules (such as trophic factors and immune modulatory substances), the so called ‘therapeutic plasticity’.

We still need to unravel key questions before clinical translation.

Gianvito Martino
San Raffaele Hospital

Although taking advantage of bystander strategies as protection from tissue injury is a very promising therapeutic use of somatic stem cells, we still need to unravel key questions before clinical translation.

DJS: In my view a major challenge in terms of translating stem cell research into clinical practice relates to the lack of an ideal therapeutic stem cell or progenitor for tissue repair and regeneration.

Currently, the vast majority of clinical trials use either autologous adult cells or allogeneic adult or fetal/newborn cells; and there are significant disadvantages to both strategies. While autologous cells are immune compatible, they are adversely affected by host factors (age, co-morbidities, risk factors, and so on) which limit their regenerative potential, often very markedly.

Although this can be avoided by the allogeneic cells from young and healthy donors, there will always be issues of immune incompatibility which likely prevent long-term engraftment without the use of immunosuppression which creates another set of problems.

Which area of stem cell research do you predict will see significant development within the next 5-10 years, and why?

GM: Several stem cell-based clinical trials are on-going worldwide despite the lack of any consensus on the best way to standardize protocols required to expand any stem cells (embryonic vs. fetal vs. adult) in vitro under good manufacturing practice conditions.

These protocols should carefully take into account not only potential sources of infection but also, and more importantly, stem cell tumorigenicity; thus, nowadays stem cell-based clinical trials should be limited to Phase I or Phase II studies.

Indeed, to substantiate the results of these types of clinical trials and to predict any stem cell-based long-term toxicity and/or side effects, it would be crucial to develop more robust imaging technologies capable of monitoring trafficking and fate of stem cells once transplanted in vivo.

So far, cell traffic monitoring technologies are based on human-grade tracers (e.g. iron based) whose in vivo specificity and sensitivity is still poor.

DJS: It is my hope that in the short-term, 3-5 years, we will have made significant progress in developing approaches to achieve high levels of cell persistence and engraftment after delivery, in order to begin to leverage some of the potential of stem cell therapy for tissue and organ regeneration and translate this into more effective clinical cell therapy strategies.

I believe that effective strategies will be developed to enhance adult stem and progenitor cell activity and overcome the deleterious effects of host factors on autologous cell regenerative potential.

Duncan J Stewart
Ottawa Hospital Research Institute

In addition I believe that effective strategies will be developed to enhance adult stem and progenitor cell activity and overcome the deleterious effects of host factors on autologous cell regenerative potential.

In the next 5-10 years it is my expectation that reliable ways to safely harness the potential of iPSCs technologies will be developed that will allow the translation of this powerful regenerative technology into clinical applications for direct organ repair or regeneration.

What would you say are the most important questions we still need to answer?

GM: The most important question we still need to answer is to find the best way to conduct stem cell-based trials in humans in order to have informative and comprehensive results.

A general consensus among clinicians, scientists, scientific societies and patients’ associations would be more than welcome and could contribute to speeding up bench-to-bedside transplantation of new emerging therapies.

Coordinative and standardized efforts would avoid generating results on few patients that can be informative from a safety point of view but worthless to robustly prove the efficacy of any stem-cell based therapy.

DJS: We still need to understand better the endogenous mechanisms that orchestrate tissue repair and regeneration, and why adult mammals, unlike other species of vertebrates, lose so significantly the capacity for full and adaptive tissue repair.

This likely will result in a new appreciation of the inter-relatedness of the immune and ‘healing’ systems, which will no doubt lead to exciting possibilities to enhance the body’s own reparative potential.

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