New Research Capitalizes on Therapeutic Promise of Programmed Cell Death

March 7, 2019

Technion Associate Professor Yaron Fuchs is the 2018 grand prize winner of the Sartorius & Science Prize for Regenerative Medicine & Cell Therapy, for work that reveals a role for programmed stem cell death in wound healing and tissue regeneration. The findings, described in his prize-winning essay, “The therapeutic promise of apoptosis,” could potentially pave the way to novel regenerative medicine and tumor therapies that target stem cells undergoing apoptosis — a type of programmed cell death.

Adult stem cells are characterized by their ability to self-renew and transform into distinct cell types, positioning them as critical drivers of tissue replenishment and repair. While great strides have been made in researchers’ understanding of the many molecular pathways that control the fate and function of stem cells, very little is known regarding the specific processes underlying their elimination.

To address such unknowns, Fuchs, who now heads the Laboratory of Stem Cell Biology and Regenerative Medicine at the Technion Israel Institute of Technology in Haifa, Israel, further investigated how seemingly “immortal” stem cells committed cellular suicide. He closely examined the proteins involved in apoptosis using a model system known to be dependent on stem cells: the hair follicle.

Fuchs discovered that loss of ARTS in mice, a protein involved in promoting apoptosis, resulted in hair follicle stem cell expansion and led to a dramatic improvement in skin repair. Mice lacking ARTS were able to regenerate hair follicles and formed smaller scars following wound infliction. What’s more, inactivation of the protein XIAP, which is targeted by ARTS, reversed these observations and impaired wound healing.

Fuchs verified that ARTS and XIAP exerted similar effects in the intestinal epithelium, a system rapidly replenished by actively dividing stem cells. In this context, loss of ARTS function also protected intestinal stem cells against apoptosis, increased their numbers, and enhanced intestinal regeneration.

“These studies demonstrate the importance of apoptosis in restricting stem cell expansion and enabling proper repair, suggesting that it serves as a defense mechanism against irreparably damaged stem cells and the emergence of cancer. The findings also suggest that transiently targeting pathways that encourage apoptosis in hair follicle or intestinal stem cells may offer therapeutic benefits to promote wound healing and regeneration,” said Fuchs.

In Fuchs’ award-winning essay, which will be published in the March 8 issue of Science, he highlights his quest to understand how epidermal stem cells use apoptosis-promoting proteins. Fuchs observed that a large number of proliferating cells within the sebaceous gland (a mini-organ that releases oily secretions) expressed an active form of caspase-3, a protein that triggers programmed cell death. Interestingly, these cells did not show any of the hallmark morphological characteristics of an apoptotic cell.

To Fuchs’ surprise, deletion of caspase-3 caused reduced proliferation and cell number, decreased organ size, and impaired sebaceous gland regeneration. Intrigued by this result, Fuchs found that caspase-3 controls the activity of YAP, a fundamental regulator of tissue regeneration and organ size.

“This discovery is particularly important, as it sheds light on standard-of-care cancer treatments like radiation and chemotherapy, which intentionally accelerate caspase-3 activity to execute tumor cell apoptosis. It also may hold promise in other applications, such as promoting wound healing by manipulating caspase-3,” said Fuchs.

“Stem cells are well known to promote tissue regeneration, but it’s less clear how stem cell elimination could impact disease,” said Science biomedicine editor Dr. Priscilla Kelly, who chaired the prize jury. “Dr. Fuchs revealed the unexpected connection between cell death pathways and the ability of stem cells to govern wound healing, skin repair and tumor growth. This is an excellent example of how state-of-the-art research can advance regenerative medicine and model new therapeutic interventions.”

Fuchs noted that he is currently in the process of developing specific inhibitors and activators of apoptotic proteins to improve stem cell-dependent skin and intestinal regeneration. Ongoing work indicates that the interplay between caspase-3 and YAP contributes to both skin wound healing and tumorigenesis. As such, his team is currently developing novel strategies for targeting caspase-3 activation in different tumor settings and regenerative models.

Next steps will include zeroing in on the myriad of molecular signals emanating from apoptotic cells, to better understand the effect they have on their surrounding environment. Fuchs hopes to harness such processes to drive tissue regeneration and block tumor development. Taking a different research direction, too, he seeks to uncover new stem cell populations, pinpointing the role they play in tissue homeostasis, repair, and tumor formation.

Established in 2017, the Sartorius & Science Prize for Regenerative Medicine & Cell Therapy — now in its second year — is an annual prize geared toward researchers focused on basic or translational research that advances regenerative medicine and cell therapy (including cell-, gene-, or immunotherapy, tissue engineering, and materials engineering). The winner is awarded $25,000 and publication of his or her essay in Science. The award is announced and presented at a ceremony for which Sartorius will provide financial support to help enable the grand prize winner to attend the ceremony.

Fuchs, along with all finalists, will be recognized during an award ceremony for invited guests only the evening of 25 April at AAAS Headquarters in Washington, D.C.
2018 Grand Prize Winner

Yaron Fuchs, for his essay “The therapeutic promise of apoptosis.” Yaron Fuchs received his undergraduate degree from Haifa University and pursued a direct Ph.D. track at the Technion Israel Institute of Technology. He next carried out his postdoctoral research at Rockefeller University and Howard Hughes Medical Institute. Upon completion, he returned to the Technion Israel Institute of Technology, where he now heads the Laboratory of Stem Cell Biology and Regenerative Medicine. His research is focused on different modes of cell death and how they regulate diverse aspects of stem cell biology and stem cell-dependent processes.
Finalist Daniele Tauriello, for his essay “From poor prognosis to promising treatment.” Daniele Tauriello studied at Utrecht University, the Netherlands, and did his Ph.D. at the University Medical Centre Utrecht. Dr. Tauriello has been a postdoctoral fellow at IRB Barcelona, Spain, working on the role of TGF-β in the tumor immune micro-environment in colorectal cancer metastasis. This year, he will set up his lab at the Radboudumc, Radboud Institute for Molecular Life Sciences, in Nijmegen, the Netherlands.

Finalist Ritu Raman, for her essay “Modeling muscle.” Ritu Raman received her undergraduate degree from Cornell University and her Ph.D. from the University of Illinois at Urbana-Champaign. Dr. Raman is currently a postdoctoral fellow at the Massachusetts Institute of Technology where she is developing and integrating novel responsive biohybrid materials into implantable devices.

Finalist Florian Bentzinger, for his essay “Best supporting actors.” Florian Bentzinger received his undergraduate degree and Ph.D. from the University of Basel in Switzerland. Following his post-doctoral studies at the Ottawa Hospital Research Institute in Canada, Dr. Bentzinger moved back to Switzerland and joined the Nestlé Institute of Health Sciences. In 2016 he was appointed as an assistant professor at the Université de Sherbrooke in Canada where he is conducting research on the skeletal muscle stem cell niche in health and disease.

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