Frontiers in Regenerative Medicine: 2019 Innovators in Science Award Symposium

Induced pluripotent stem cells (iPSCs) can proliferate almost indefinitely and differentiate into multiple lineages, giving them wide medical application. As a result, they are being used for new cell-based therapies, disease models and drug development around the world.

In 2014, the world’s first clinical study using iPSCs began for the treatment of age-related macular degeneration. iPSC studies have also made major progress for other disorders, such as Parkinson’s disease, giving rise to the expectation that iPSC-based regenerative medicine will be widely used in the near future.
　
Other applications of iPSCs are drug screening, toxicity studies and disease modeling. In 2018, a new drug screening system using iPS cells for fibrodysplasia ossificans progressiva (FOP) was reported, revealing one drug candidate to go to clinical trial to treat FOP patients.

Over the past decade, iPSCs research has made great progress. Despite the still various hurdles to be overcome, iPSC-based science is certainly moving forward for delivering innovative therapeutic options to the patients with intractable diseases.

The epithelial tissues that line our body routinely experience inflammation inducing pathogenic and noxious agents while harmoniously housing a myriad of resident microbial communities. The mechanisms and consequences of how epithelial tissues, and in particular their long-lived stem cells, sense, respond to, and remember such encounters are only now beginning to unfold. I discuss the crosstalk between immune cells, epithelial stem cells, and commensal microbes and its importance for epithelial health and regeneration. Understanding these dynamic interactions may provide unique means of boosting epithelial barrier function and healing by modulating immune and microbial signals perceived by stem cells.

LAMB3-dependent generalized Junctional Epidermolysis Bullosa (JEB) was targeted by transplantation of epidermal cultures originated from transgenic epidermal stem cells. We report life-saving regeneration of the entire epidermis on a seven-year-old JEB child suffering from a devastating form of JEB. The regenerated transgenic epidermis remained stable throughout the entire follow-up period and did not form blisters, even upon shear force. The proviral integration pattern was maintained in vivo and epidermal renewal did not cause any clonal selection. Clonal tracing showed that the human epidermis is sustained by a limited number of long-lived stem cells, detected as holoclones, that can extensively self-renew and produce short-lived progenitors that replenish terminally differentiated keratinocytes.

The first in-human application of induced pluripotent stem cells (iPSC) began in 2014 for retinal diseases. Understanding of the risks and benefits of stem cell treatment by our team of experts in basic research, genetic diagnostics, and clinical surgery enabled us to bring this iPSC technology to clinical phases within 5 years of its invention. This comprehensive approach, applied from early stages, not only creates a short path to clinical application but also informs strategies to improve functional and social outcomes for visually impaired patients. Furthermore, I will discuss how recent advancements in iPSC differentiation protocols using AI robotic platforms have enabled novel biological applications.

Multipotent self-renewing hematopoietic stem cells (HSCs) maintain hematopoiesis throughout life. The mechanism of such striking capability of HSCs remains unanswered, mainly because of the paucity of HSCs in the bone marrow. Ex vivo expansion has been a holy grail of HSC research, yet, no such system exists despite numerous studies over the decades. Here we developed a simple platform to expand functional mouse HSCs ~900-fold over 28-days using a chemically-defined, albumin-free culture conditions. The large numbers of ex vivo expanded HSCs enabled non-myeloablative HSC transplantation, curative for immunodeficient recipients. Thus, the ex vivo expansion of HSCs provides a platform not only to interrogate HSC self-renewal and lineage commitment but also suggests a novel approach in clinical HSC transplantation.

Pluripotent cells emerge as a naïve founder population in the mammalian blastocyst. They then develop capacity for germline and somatic specification prior to lineage priming and differentiation. Mouse embryonic stem cells and post-implantation epiblast stem cells (EpiSC) represent the early naïve and late primed stages of pluripotency respectively. Between these two stages a formative transition occurs, in vitro and in the embryo, through which competence is acquired for multi-lineage induction. This transition is driven by three complementary transcription factor activities which orchestrate dismantling of the naïve pluripotency gene regulatory network and commissioning of the formative state.

This moderated panel discussion and audience Q&A will focus on mechanisms of development and regeneration. The panel consists of members of the Award’s Scientific Advisory Council and Jury. The SAC provides scientific guidance to the Innovators in Science Award program and nominates candidates for the prize. The Jury is independently selected by the New York Academy of Sciences and chooses the award winners.