Abstract
IFN- produced by T cells directly induces intestinal stem cell death upon inflammation-induced intestinal injury (see the related Research Article by Takashima et al.).
Intestinal regeneration upon tissue damage is fueled by intestinal stem cells (ISCs) residing in the crypt bottom of the epithelium and marked by the gene Lgr5 (1, 2). There is growing evidence that tissue repair is at least partially mediated by a regenerative inflammatory response (3, 4). How inflammation-induced intestinal injury influences ISCs and their microenvironment (stem cell niche) remains poorly understood. In this issue of Science Immunology, Takashima et al. (5) explore the changes in the ISC niche in vivo upon T cellmediated injury as a model of graft-versus-host disease (GVHD) and in vitro using organoid T cell cocultures. Although earlier studies already implicated interferon- (IFN-) as a negative regulator of intestinal epithelial homeostasis (68), Takashima et al. now demonstrate that IFN- directly acts on ISCs by triggering apoptosis.
In an allogeneic bone marrow transplant (BMT) model, Takashima and colleagues found that ISC numbers per intestinal crypt were markedly reduced in mice receiving bone marrow alone or bone marrow and T cells when compared with normal control mice. While the ISCs in the mice receiving only bone marrow recovered 7 days later, the ISC numbers remained reduced in those mice also transplanted with donor T cells. Of note, Paneth cell numbers were also reduced after ISC depletion. The numbers of organoids established from the intestines of mice 10 days after BMT recovered back to that of control mice, whereas the organoid forming capacity from crypts of mice after combined transplantation of bone marrow and T cells remained significantly lower. Similar in vivo and in vitro results were obtained when autoreactive T cells were transplanted, pointing to a common feature of T cellmediated intestinal injury.
As seen by three-dimensional confocal microscopy, intraepithelial T cells (CD3+ IELs) preferentially localized to the villus region, whereas lamina propriaassociated T cells (CD3+ LPLs) were equally distributed along the crypt-villus axis of control mice (Fig. 1A). Conversely, mice receiving bone marrow and allogeneic T cells showed a progressive increase in the density of both CD3+ LPLs and CD3+ IELs in the crypt region.
To identify signaling molecules that cause the loss of ISCs in this model, Takashima and colleagues performed several elegant murine and human epithelial organoid coculture experiments. Murine nave allogeneic T cells did not impair murine intestinal organoid numbers, whereas alloreactive T cells effectively reduced organoid numbers. Likewise, human allogeneic cytotoxic T cells robustly inhibited human intestinal organoid forming efficiency. Even bead-activated autologous T cells suppressed human intestinal organoid growth. The authors then proceeded to screen for potential pathways mediating cytotoxicity. Organoids cocultured with T cells in the presence of antiIFN- neutralizing antibodies showed normal growth. Although IFN- receptor (IFN-R)depleted T cells were still able to affect organoid viability, IFN-Rdepleted organoids were resistant to T cellmediated killing. Organoid toxicity by IFN- was also observed in the absence of T cells. Live imaging confirmed the progressive ISC depletion upon organoid exposure to IFN-. Treatment of organoids with the immunosuppressive JAK1/2 inhibitor ruxolitinib robustly preserved numbers of both organoids and ISCs in the presence of IFN-, irrespective of whether the organoids were cultured alone or together with T cells. The authors additionally demonstrated that JAK1-depleted organoids are resistant to IFN- treatment. Further downstream, ruxolitinib prevented STAT1 phosphorylation by IFN- in intestinal crypts, and, in line, STAT1-depleted organoids were resistant to growth suppression in response to IFN- treatment.
IFN-treated organoids showed reduced expression of ISC marker genes. ISCs underwent apoptosis in vitro in a direct response to IFN-. Next, the authors confirmed in vivo that ISC numbers did not change upon transplanting allogeneic bone marrow and T cells when treating mice with IFN- neutralizing antibodies. Likewise, ruxolitinib treatment protected ISCs from T cellmediated killing in vivo. Donor T cells, particularly T helper 1 cells, were activated and IFN-+. Transplanting IFN-depleted allogeneic T cells robustly reduced the ISC loss and allowed epithelial cell proliferation to increase.
Takashima and colleagues lastly investigated whether IFN- directly induces ISC apoptosis. Using tissue-specific depletion of IFN-R1, the authors found that epithelial loss of the receptor protects from the immune-mediated GVHD phenotype. IFN-R1 is expressed by both ISCs and Paneth cells, the epithelial component of the ISC niche (9). However, Paneth celldeficient organoids remained sensitive to both IFN- and allogeneic T cellmediated cytotoxicity. Likewise, T cells were able to reduce the number of organoids containing IFN-R1deficient Paneth cells, whereas organoids containing IFN-R1deficient ISC were protected from cytotoxicity. The authors demonstrated in further experiments that IFN- directly induces ISC apoptosis independent of Paneth cells (Fig. 1, B and C).
The study by Takashima et al. extends our knowledge on signaling between ISCs and immune cells, identifying ISCs as direct targets of IFN- secreted by T cells in immune-mediated intestinal damage (as caused by GVHD). In the 2015 study by Lindemans et al., this group already identified that interleukin-22 (IL-22) secreted by group 3 innate lymphoid cells (ILC3s) directly stimulates ISCs to proliferate and regenerate the intestinal epithelium upon inflammation-induced intestinal injury (4). Modulating the effects of T cellderived IFN- on ISC, for instance, by suppressing JAK/STAT signaling via ruxolitinib treatment, may provide a new therapeutic avenue to reducing GVHD-induced damage of the intestinal epithelium (10).
(A) ISCs maintain adult homeostasis of the intestinal epithelium. T lymphocytes patrol the intestine. (B) Takashima et al. show that in GVHD as modeled by BMT and aberrant activation of T lymphocytes, T cellderived IFN- directly acts on ISCs and induces apoptosis via JAK/STAT signaling. (C) Disease progression results in marked intestinal damage due to loss of ISCs and their niche.
Acknowledgments: Funding: K.K. is a long-term fellow of the Human Frontier Science Program Organization (LT771/2015). Competing interests: H.C. and K.K. are named inventors on patents or patents pending on Lgr5 stem cellbased organoid technology.
Read this article:
IFN-: The T cell's license to kill stem cells in the inflamed intestine - Science
- Stem Cell Science and Human Research Studies Ahead of Cargo Arrival - NASA Blogs - February 21st, 2024
- Harvard Stem Cell Institute (HSCI) - December 29th, 2023
- Stem cell - Wikipedia - December 29th, 2023
- A Look Inside Stem Cells Helps Create Personalized Regenerative ... - May 17th, 2023
- Heart disease study shows hope for stem cell treatment - March 4th, 2023
- Focus On Stem Cell Research | National Institute of Neurological ... - March 4th, 2023
- Stem Cell Research: Argumentative Essay - Free Essay Example - Edubirdie - March 4th, 2023
- Automated Cell Culture Systems Market Size to Hit USD 12.43 Billion by 2033; Growing Stem Cell Research & Development and Increasing Prevalence of... - October 21st, 2022
- NIH Guidelines for Human Stem Cell Research - October 13th, 2022
- Ethics of Stem Cell Research - Blue Marble Space Institute of Science - October 13th, 2022
- Global Cell Therapy Market Report (2022 to 2028) - Featuring Thermo Fisher Scientific, MaxCyte, Danaher and Avantor Among Others -... - October 13th, 2022
- Stem Cell Therapy Market (2022-2029) Size Will Escalate Rapidly in the Near Future: Osiris Therapeutics, Molmed - Digital Journal - October 13th, 2022
- Fighting One Disease or Condition per Day - Daily Kos - October 13th, 2022
- The Issue of Tissue: Getting to the Source of the HIV Reservoir - amfAR, The Foundation for AIDS Research - October 13th, 2022
- Cell Isolation Global Market Report 2022: Significant Growth in the Medical and Pharmaceutical Industries Driving Sector - ResearchAndMarkets.com -... - October 13th, 2022
- Nancy and Geoffrey Stack Family Foundation give $2 million to UCI Health - UCI News - October 4th, 2022
- Cell Isolation Market is expected to generate a revenue of USD 20.50 Billion by 2028, Globally, at 15.70% CAGR: Verified Market Research -... - September 25th, 2022
- Creating stem cells from minipigs offers promise for improved treatments - University of Wisconsin-Madison - September 16th, 2022
- Hemostemix Announces the Appointment of Dr. Renzo Cecere, MD, FRCSC to Its Scientific Advisory Board - Yahoo Finance - September 16th, 2022
- Genomics study identifies unique set of proteins that restores hearing in zebrafish - National Institutes of Health (.gov) - September 16th, 2022
- Discovered Key Mechanisms to Improve Intestinal Regeneration and Alleviate the Side Effects of Radiotherapy - Imaging Technology News - September 16th, 2022
- Global Cell Expansion Market Size to Grow at a CAGR of 15% during the Forecast Period 2022-2027 - Digital Journal - September 16th, 2022
- The American Cancer Society Awards $2.1 Million to Montefiore Einstein Cancer Center to Support Cancer Research and Tackle Inequities - Yahoo Finance - September 16th, 2022
- Hair Restoration Market | Stem Cell hair Restoration and Low-level Laser Therapy (LLLT) segment are Expected to Witness Significant CAGR - MDC... - August 30th, 2022
- Stem Cell Therapy for Parkinson's: Current Developments - Healthline - August 5th, 2022
- 'Off the shelf' CAR T cells for cancer treatment? - Boston Children's Answers - Boston Children's Discoveries - August 5th, 2022
- Inflammation accelerates aging of the hematopoietic system - EurekAlert - August 5th, 2022
- New patent-pending method mass-produces antitumor cells to treat blood diseases and cancer - Purdue University - August 5th, 2022
- Cell Therapy Technologies Market worth $8.0 billion by 2027 - Exclusive Report by MarketsandMarkets - PR Newswire - August 5th, 2022
- Twenty-Five Years After My House Call To Dolly: What Have We Learned About Cloning And How Did We Learn It? - Forbes - August 5th, 2022
- Tendon Stem Cell Therapy Market is Booming Worldwide with Strong Growth Prospects | Cellualar Dynamics, Cellectis, International Stem cell... - July 27th, 2022
- [Pangyo Bio & Medical] Theragen Bio discovers MAST4 Protein that Regulates Bone Cartilage Development For 'The First Time in The World' - Digital... - July 27th, 2022
- Cell Culture Media Market Size Worth $10.2 Billion by 2030: Grand View Research, Inc. - PR Newswire - July 27th, 2022
- Cryopreservation Equipment Market Report 2022-2028: Importance of Cryopreservation for Success of Cell-Based Therapies Presents Opportunities -... - July 27th, 2022
- Whitmer axes stem cell research, pregnancy center funding over abortion access concerns - MLive.com - July 19th, 2022
- Stem Cell - National Human Genome Research Institute Home - July 11th, 2022
- Induced Pluripotent Stem Cells (iPS) | UCLA Broad Stem Cell Center - July 11th, 2022
- Global 3D Cell Culture Market To Be Driven By Growing Impact Of Economy On Regenerative Medicine, Emerging Applications Of Gene Therapy During The... - July 11th, 2022
- New Combination Therapy Effective in Pediatric Leukemia - Technology Networks - June 22nd, 2022
- MIT Pioneers Technology To Grow Customizable Wood Products in the Lab With Little Waste - SciTechDaily - June 22nd, 2022
- First-of-its-Kind Stem Cell and Gene Therapy Highlighted at Annual Stem Cell Meeting - Newswise - June 13th, 2022
- Scientists hope this injectable stem cell gel can repair heart attack damage and avoid transplants - Euronews - June 13th, 2022
- Axol Bioscience Introduces CiPA-Validated Human Stem Cell-Derived Ventricular Cardiomyocytes to Help Improve Drug Discovery - Business Wire - June 13th, 2022
- Fasting has pros and cons for muscle repair in mice - Futurity: Research News - June 13th, 2022
- First Clinical Trial of Transplanted 3D Ear Using Human Cells Proves Successful via 3DBio Therapeutics - Tech Times - June 4th, 2022
- Insights on the Dimethyl Sulfoxide (DMSO) Global Market to 2027 - Expanding Research and Development in Stem Cell Transplantation to Benefit Demand... - May 15th, 2022
- Scientists Rejuvenate Skin Cells by 30 Years, with Pioneering Potential - BioSpace - May 15th, 2022
- Global Flow Cytometry Market is expected to grow at a lucrative rate of 8% to reach $11 billion by 2026 A Robust Tool that Defines New Era for... - May 15th, 2022
- Global Mesenchymal Stem Cells Market Research Report to 2027 - Featuring Astellas Pharma, Axol Biosciences and BrainStorm Cell Therapeutics Among... - May 2nd, 2022
- Researchers share insights about the mechanisms of human embryo and create method to develop transcriptionally similar cells in tissue culture -... - May 2nd, 2022
- Flow Cytometry Market is Estimated Drive the Industry Growth Across World in Coming Year 2030 Queen Anne and Mangolia News - Queen Anne and Mangolia... - May 2nd, 2022
- Mini-heart chamber beats on its own just like the real thing - Futurity: Research News - May 2nd, 2022
- The Case Against Embryonic Stem Cell Research: An ... - April 6th, 2022
- Burst of accumulated zinc shows how the mineral boosts immune function, suggesting ways to improve health - EurekAlert - April 6th, 2022
- Hoyer Statement on the Retirement of Congressman Fred Upton - Majority Leader - April 6th, 2022
- 11 Stem Cell Research Pros and Cons Vittana.org - March 25th, 2022
- Research Associate, Cancer and Stem Cell Laboratory job with UNIVERSITY OF SYDNEY | 287031 - Times Higher Education - March 25th, 2022
- Google still has a problem with stem cell and unproven therapies - STAT - STAT - March 25th, 2022
- Medeze Named Frost & Sullivan's 2021 Company of the Year in the Southeast Asia Stem Cell Banking Industry - PR Newswire - March 25th, 2022
- Bone Marrow-Derived Stem Cells (BMSCS) Market Report- Growth in Future with Size, Share, Growth, and Key Companies Analysis Cord Blood Registry... - March 25th, 2022
- Autologous Stem Cell and Non-Stem Cell Based Therapies Market Future Business Opportunities 2022-2028 | Caladrius Biosciences, Vericel Corporation,... - March 25th, 2022
- Cell Therapy Market Trends, Revenue, Key Players, Growth, Share and Forecast Till 2028 Reports and Data - Digital Journal - March 25th, 2022
- This Fancy AF Face Cream Was Invented by a Stem Cell Researcher - VICE - March 25th, 2022
- Freeze Thaw Chambers Market: The cryopreserved products segment is expected to drive the growth of the market - BioSpace - January 5th, 2022
- As Nave as They Get - Weizmann Wonder Wander - News, Features and Discoveries - Weizmann Institute of Science - January 5th, 2022
- Jake's mice: Searching for answers to the puzzle of autism - huntingdondailynews.com - January 5th, 2022
- Primary Cells, Stem Cells, Culture Media and Reagents Market to Witness Rapid Growth by 2029 | BrainStorm Cell Therapeutics Inc., Caladrius... - January 5th, 2022
- Gait Rehabilitation System Market: Rising incidence of various neurological disorders to drive the market - BioSpace - January 5th, 2022
- ARVO Foundation Announces 2022 Bert M. Glaser, MD Award for Innovative Retina Research Recipient - Newswise - January 5th, 2022
- Communication between cells plays a major role in deciding their fate - EurekAlert - December 24th, 2021
- The 10 Most Compelling Research Stories of 2021 - BioSpace - December 24th, 2021
- MRC Lead Apologizes Following Bullying Allegations - The Scientist - December 24th, 2021
- California Proposition 14, Stem Cell Research Institute ... - November 22nd, 2021
- Ethical Issues in Stem Cell Research - PubMed Central (PMC) - November 22nd, 2021
- Opinion | How Covid Raised the Stakes of the War Between Faith and Science - The New York Times - November 8th, 2021
- What is Stem Cell Research? | The Benefits of Stem Cell Research - October 5th, 2021
- An Overview of Stem Cell Research | The Center for Bioethics ... - October 5th, 2021
- Stem Cell Research: Uses, Types & Examples - October 5th, 2021
- Stem Cells | National Institutes of Health (NIH) - October 5th, 2021
- Stem cells: Therapy, controversy, and research - October 5th, 2021