Basic immune mechanisms in hematopoietic stem cell transplantation
Understanding the mechanisms that sustain immunological non-reactivity are basic for maintenance of tissue. While most of the transplantation rejection happens due to the adaptive immune response, the pro-inflammatory response of the innate immunity is necessary for the activation of adaptive immunity -both in syngeneic and allogeneic settings. Recently we identified the molecular and cellular framework underlying innate immunity loss of tolerance to allogeneic tissues within a natural Botryllus schlosseri chimera. It is an integrated function of both homeostatic cell turnover and licensing of cytotoxic effector cells. Studying pathways and mechanisms that direct successful innate immunity tolerance in a relatively simple model organism, B. schlosseri, can provide novel insights into these immune processes in humans.
B. schlosseri has a few levels of innate immunity responses: non-inflammatory program cell removal (during the weekly cycle), acute rejection, allogeneic resorption (chronic rejection). Additionally, we have recently developed the B. schlosseri as a full model for studying hematopoietic stem cell (HSC) transplantation, including isolation of HSC, characterizing the immune interaction including cytotoxic cells that govern the allogeneic response, finding the HSC-niche, and showing the homology of the B. schlosseri HSC and their niche to the human HSC and the hematopoietic bone marrow, respectively.
We study the functional mechanisms affecting innate immunity tolerance in a model system of B. schlosseri.
Finally, we test our findings in mammalian immune systems and hematopoietic stem cell transplantation.
This project is funded by the Israel Science Foundation (ISF).
Rosental et al. Nature, 2018
Corey and Rosental et al. PNAS 2016
Immune-based tissue rejection or regeneration
In collaboration with Prof. Bo Wang, Stanford University, Bioengineering
We currently work with Prof. Bo Wang from Stanford University on the planarians' immune system characterizing the cellular immunology. We are modeling the immune system inflammatory response that can go to two different directions: i) a resolution mechanism that is an anti-inflammatory and pro-regeneration, or the “tipping point” ii) a pro-inflammatory response that is destroying the tissue. We are looking at a cellular level and the ratios between, developing progenitor populations, damaged cells, phagocytic cells, and cytotoxic cell populations. This work is combining in-vivo, in-vitro and mathematical modeling to understand the base at the “tipping point” of the immune response. We have received for this work the Human Frontiers Science Program (HFSP) research grant.
Study stem cell transplantation in non-classical model organisms
Coral Stem Cells for Treatment, Recovery, and Regeneration to Create Heat Resilient Corals.
Coral reefs are one of the most valuable ecosystems on this planet, responsible for feeding millions of people and fostering biodiversity in the oceans. However, the negative effects of climate change on the world’s oceans are becoming more apparent each day; and coral reefs are disappearing at an alarming rate. Bleaching and coral death occurs over a short period of time and therapeutic and restorative technology is needed to save the world’s coral reefs.
Stem cells are self-renewing, developmental units capable of regeneration that can differentiate into different cell types and tissues and are considered to be fundamental units of natural selection. Because they have the potential for differentiation to multiple cell types, including hematopoietic cells and germline cells, stem cells have unique therapeutic potential and, in some organisms, including colonial invertebrates such as corals, can regenerate whole body structures many times during life. Although little is understood about stem cells within corals, the conserved function of these cells in different organisms suggests that stem cells would have regenerative capabilities in corals. For example, transplantation of stem cells from heat resistant corals to susceptible corals could confer resilience to the host coral colony and help to regenerate tissue structures.
Improved knowledge about stem cell isolation, transplantation and propagation will provide technology that is fundamental for repair, recovery, and regeneration of thermo-tolerant corals. The proposed work would lay the groundwork for the application of stem cell technology to the daunting problem of coral conservation.
We have received for this work the European Research Council (ERC) grant.
Additionally, together with our collaborator, Dr. Nikki Traylor-knowles, this project is part of a bigger collaboration by Revive & Restore for developing cellular, molecular and genetic tools for saving coral reefs: https://reviverestore.org/projects/advanced-coral-toolkit/
Preventing life-threatening cardiac inflammation- Hikeshi Project
The Hikeshi protein is a highly conserved protein crucial in the heat shock response mechanism, responsible for the nuclear localization of the well-known HSP70. Our research follows a few Asheknazi-Jewish and Palestinian families in Israel who carry an extremely rare point mutation in the Hikeshi gene, which results in a recessive disease with neurodevelopmental effects, as well as with life threatening cardiac inflammation associated with elevated fever.
We hypothesize that the cardiac inflammation results from an excessive immune response due to the impaired heat-shock mechanism. Our lab specializes in the characterization of immune responses, including cytokine release, cell activation, phagocytosis and cytotoxicity. We have reprogramed induced human pluripotent stem cells (iPSCs) from patient cells, which we are differentiating to cardiomyocytes to understand the cardiac inflammation associated with elevated fever.
Due to the multifaceted nature of this mutation, collaboration is key, and this project is in collaboration with multiple labs, hospitals and physicians across Israel, with different specialties and capabilities, including the two additional researchers here at the Stem Cells and Regenerative Medicine center, Dr. Gad Vatin and Prof. Yoram Etzion. Eventually, we, as a collaborative consortium, aspire not only to elucidate the many mechanisms underlying the different phenotypes of this mutation but also hope to offer a therapeutic solution to the people carrying it.
Study immune systems in non-classical model organisms
Hexacorallians immune system response in heat stress.
In this additional project in corals and anemones, we characterize the immune cells in those models and their functions in heat stress conditions. We hypothesize that the immune system of the corals is taking part in the bleaching process during heat stress conditions.
This project is in collaboration with Dr. Traylor-Knowles from the University of Miami.
Together with Dr. Nikki Traylor-knowles, we have received the NSF-BSF grant for this work.