Research in the Weissman Lab
Stem cell biology in health and disease and the development of macrophage-based immunotherapy:
Tissue stem cells are rare and only make the maturing and mature cells of the tissue they serve [HSC for blood, CNS stem cells for brain, skeletal stem cells for bone and cartilage and bone marrow inductive microenvironments, etc.]. Within a tissue they are the only cells that can self-renew throughout life. While the usual outcome is tissue and organ homeostasis, stem cells can accumulate and propagate mutations over many years, and those mutant stem cells can contribute to disease. Mutations that arise in any non-stem cell in a tissue are lost via the limited lifespan of non self-renewing cells. In leukemic cells, the lab discovered up-regulation of CD47 that acts as a dont eat me signal for macrophages and allows cancer cells to evade an immune response. They developed anti-CD47 as a cancer immunotherapy and continue to investigate how macrophages recognize and eliminate unhealthy cells, with a prospect of advancing medicine.
The biology of HSC and their niche:Weissman was first to identify, prospectively isolate, and transplant hematopoietic [blood-forming] stem cells, called HSC from mice and humans. HSCs generate and regenerate the entire blood and immune systems throughout life. The lab has then isolated and studied the progenitor steps between the HSC and each of the blood cell type produced. He has also traced the formation of HSC during mouse embryogenesis and fetal development, and for all of these candidate stem and progenitor cells has optimized single cell RNAseq and utilized ATACseq and CHIPseq to elucidate the steady state expression of suites of genes that characterize each stem and progenitor cell in both species. These technologies have allowed the lab to propose candidate genes whose expression either characterize the molecular fingerprints of those cells, but point toward the events required for stem cell self-renewal and for differentiation to the next cell in the developmental pathways.To study HSC and their niche, the lab generated unique reporter mouse models in which HSC expressing a fluorescent marker, HoxB5.mCherry exist as single cells attached to a subtype of bone marrow blood vessel cell, surrounded also by stromal cells from the skeletal stem cell. In parabiotic pairs, mice with a joined vasculature to each other, these marked HSC migrate from one mouse to the partner bone marrow to occupy one of these vascular niches. Working out how these interactions and migrations occur and the molecules that are responsible is a current interest of the lab.
Human Brain Stem Cells [CNS SC]: Weissman and colleagues identified and prospectively isolated human fetal brain stem cells, and upon their transplantation into the brains of immune deficient mice, found that these CNS SC home to mouse brain stem cell niches near the lateral ventricles and in the dentate gyrus of the hippocampus. The progeny of these human CNS SC self-renew in these niches, migrate their progeny in a site appropriate manner long distances through the brain, and differentiate to neurons, astrocytes, and oligodendrocytes in site appropriate manners as well. This allows one to begin to understand adult human CNS SC behaviors. These human CNS SC can engraft in patients and have regenerative and neuroprotective properties. Each CNS SC can be propagated in vitro into clonal spheres of CNS SC. Recently students in the Weissman lab have found how to identify, isolate grow, and transplant human CNS SC from surgical samples.
Stem Cells, Clonal Precancer Cells, and Progeny Cancer Stem Cells:Over the past 20 years theWeissman lab developed a method to identify mutations in single cells, and using that showed that preclinical progression occurs due to stepwise accumulation ofdrivermutationsin a clone of HSCsleading to clonal expansions of preleukemic HSCs, competing with normal HSC for the single HSC cell niches, with the last step forming leukemia stem cells [LSC].While random passenger mutations also occur, sometime creating new antigens; passenger mutations do not contribute to clonal expansions.The preleukemic HSC clones can become disease cells in CML, MDS, and acute leukemias.This model of preclinical cancer progression through accumulation of mutations in stem cells should apply to any somatic tissue. Work in the lab is currently focused on studying neural stem cells, their generation of oligolineage progenitors to form the brain neuropoietic tree similar to the hematopoietictree, to use them for study single cell RNAseq to discover genes enforcing or preventing each step of differentiation, and to identify genes that allow their progeny to self-renew, migrate, and differentiate in a site-appropriate manner. A current project in the lab is to isolate CNS-SC from surgical samples of brain tumors resected from patients with incurable brain cancers, to look for the order in which driver and passenger mutations occur, and to use their clonal expansion to neurospheres to work out the in vivo biological consequences of each driver mutation.
Macrophage regulation and its therapeutic application:By comparing leukemic to healthy hematopietic stem cells, the Weissman lab has identified CD47 overexpression on LSC, and then on all cancers tested. They showed that CD47 is a cell surface molecule used by cancer cells to evade macrophage phagocytosis by binding to its receptor, SIRPaon macrophages. This led to the development of a new type of immunotherapy based on macrophage checkpoint inhibition through blockade of CD47 which is perhapsthe first targetexpressed on all human cancers tested. In pre-clinical research using patient-derived xenografts, we showed dramatic effects in the treatment of diverse types of human cancer with anti-CD47 antibodies or blocking agents that neutralize the inhibitory effect of CD47-SIRPainteraction and unleashes the ability of macrophages to engulf and eliminate cancer cells.Importantly, antibody blockade of CD47 did not affect normal cells expressing CD47. This suggested that cancer cells but not normal cells display an eat me signal, which they discovered to be calreticulin, a signal recognized by macrophage prophagocytic receptor CD91. Blockade of CD47 allows macrophage removal only of cells that express calreticulin on their surface. Weissman et al discovered that calreticulin is mainly produced and secreted by activated macrophages, and that it binds to nearby cancer cells through recognition of surface asialoglycans, presumably via sialic acid removing enzymes that create the calreticulin binding sites. The molecular and cellular mechanisms for this system are currently under study. The lab has also found 3 additional dont eat me molecules and their macrophage receptors.
Our findings in collaboration with the Leeper lab re Atherosclerosis:This collaboration has shown that atherosclerotic plaque formation involves the clonal expansion of arterial smooth muscle cells from local stem or progenitor cells. These cells display both CD47 and calreticulin on their surface. Treatment with anti-CD47 antibodies in a mouse model (high fat diet on a genetically susceptible background), resulted in the elimination of atherosclerotic lesions, and preliminary studies implicate this process in human atherosclerosis, a process that leads to heart attacks, stroke, aortic aneurysms, and loss of tissues in diabetic atherosclerosis.Current research in the lab continues to explore the role of macrophages in disease prevention and treatment, through understanding how macrophages recognize their target cells, and the signals that impact the ability of these cells to maintain tissue integrity and sustain a state of health.
Stem cell research in a marine model organism:At the Hopkins Marine Station, the Weissman lab has space where its been conducting stem cell research in the marine model organismBotryllus schlosseri. This model organism has very interesting stem cell biology and immunology as related above.. It is a colonial organism, in which each individual within the colony undergoes a complete regeneration cycle weekly through a process of budding. When two adjacent colonies develop vascular anastomoses, stem cells from one colony can compete with stem cells of the other; for the germline stem cells, there is always a winner and a loser strain. Practically what this means is that stem cells from one colony invade the other and can take over the germline so that the invaded colony will now produce gametes, reproductive cells, of the genotype of its neighbor.
The discovery of this process is what led Weissman to realize that stem cells can compete and to hypothesize and then prove that both spermatogenic stem cells compete in mice, and led to the concept and proof of competition in preleukemic clonal expansions, in the leukemias and in aging.
A current list of publications
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Irving Weissman Laboratory | Institute for Stem Cell ...
- BioCardia and StemCardia Announce Biotherapeutic Delivery Partnership - Diagnostic and Interventional Cardiology - March 17th, 2024
- Cynata Therapeutics' breakthrough in regenerative medicine - Finance News Network - March 17th, 2024
- New Positive Data Presented on Briquilimab Conditioning in Patients with Fanconi Anemia - GlobeNewswire - March 17th, 2024
- Novel 3D stem cell therapy to treat critical limb ischaemia - Drug Target Review - March 15th, 2024
- Breaking Boundaries: Pharmicell's Bold Vision for Healthcare Transformation and Monumental Growth - The Worldfolio - March 15th, 2024
- CuSTOM Organoid Research Evolving From Tool to Treatment - Research Horizons - Research Horizons - March 15th, 2024
- BioCardia and StemCardia Announce Partnership to Deliver Cell-Gene Therapy for Remuscularization of Heart - Cath Lab Digest - March 15th, 2024
- Calidi Biotherapeutics and City of Hope Announce Funding from the California Institute for Regenerative Medicine ... - Business Wire - March 13th, 2024
- Iron restriction keeps blood stem cells young, researchers find - Phys.org - March 13th, 2024
- Vitamin A could have a key role in both stem cell biology and wound healing: Study - Medical Dialogues - March 9th, 2024
- Trends in Stem Cell Transplantation Refusal for Myeloma Treatment - Targeted Oncology - March 7th, 2024
- Stem Cell Therapy Market (CAGR) of 31.1%, Future of Market Size Emerging Technologies and their Impact on ... - Taiwan News - March 7th, 2024
- This Swedish startup wants to reduce the cost, and controversy, around stem cell production - TechCrunch - March 6th, 2024
- Advancing stem cell therapy: The regulatory process to get to clinical trials - The Economic Times - March 6th, 2024
- Transitioning from traditional surgical methods to the innovative use of stem cells - pharmaphorum - March 6th, 2024
- 'Mini organs' are grown from human stem cells taken during the late stages of pregnancy for the first time - m - Daily Mail - March 6th, 2024
- Stem cell transplant cures man of HIV and leukemia, one of five to achieve full remission - Fox 28 - March 3rd, 2024
- Stem Cell Therapy Market to Boost USD 137.5 Billion by 2034 and Projected to grow at 32.10% CAGR with increasing ... - Yahoo Finance - March 1st, 2024
- Studies expand use of stem cell therapies - WPLG Local 10 - March 1st, 2024
- Innovative therapy targets and destroys leukemia stem cells - News-Medical.Net - February 27th, 2024
- Unlocking the Potential of Stem Cells: The Medical Revolution of the Century - EIN News - February 27th, 2024
- Pelage Pharmaceuticals Announces $16.75M Series A Financing led by GV to Revolutionize Regenerative Medicine ... - Yahoo Finance - February 27th, 2024
- Say Her Name - Henrietta Lacks, The Real Mother Of Stem - Her Campus - February 27th, 2024
- California Man Free of HIV And Cancer in Astonishing Medical Recovery - ScienceAlert - February 25th, 2024
- $93 million for research into improved health for children, young people and the aged, medical devices, mental health ... - Department of Health - February 25th, 2024
- Stem Cells in Regenerative Medicine - PMC - National Center for ... - February 24th, 2024
- The Promise and Reality of Stem Cell Therapy: What You Need to Know - Corporate Wellness Magazine - February 22nd, 2024
- Stem Cell Therapy: A Beacon of Hope for Patients with Untreatable Conditions - Corporate Wellness Magazine - February 22nd, 2024
- Leading Experts in Stem Cell Therapy: A Global Overview - Corporate Wellness Magazine - February 22nd, 2024
- Can Stem Cells Help Reverse the Effects of Aging? - Corporate Wellness Magazine - February 22nd, 2024
- Stem Cell Therapy for Cancer: Hope on the Horizon? - Corporate Wellness Magazine - February 22nd, 2024
- Stem Cells and Autism: A Closer Look at Innovative Treatments - Corporate Wellness Magazine - February 22nd, 2024
- Regrowth and Restoration: The Science Behind Stem Cell Therapy for Hair - Corporate Wellness Magazine - February 22nd, 2024
- Brain Recovery: The Role of Stem Cells in Stroke and Cerebral Palsy Treatments - Corporate Wellness Magazine - February 22nd, 2024
- Turning Back the Clock: The Science of Stem Cells in Anti-Aging - Corporate Wellness Magazine - February 22nd, 2024
- Insights into cellular therapies for cancer treatment - Drug Target Review - February 22nd, 2024
- The Role of Stem Cells in Rheumatoid Arthritis Recovery - Corporate Wellness Magazine - February 22nd, 2024
- Dr Ernesto Romeros vision transforms immunotherapy regenerative medicine into a global leader in stem cell treatment - Khaleej Times - February 22nd, 2024
- World-Renowned Doctors Leading the Way in Stem Cell Research and Treatment - Medical Tourism Magazine - February 20th, 2024
- Choosing the Best: A Guide to America's Premier Stem Cell Therapy Providers - Medical Tourism Magazine - February 20th, 2024
- Navigating Through the Possibilities of Stem Cell Treatment for Eye Disorders - Medical Tourism Magazine - February 20th, 2024
- Global Leaders in Stem Cell Therapy: Where Excellence Meets Innovation - Medical Tourism Magazine - February 20th, 2024
- Excellence in Stem Cell Treatment: How the US is Pioneering Global Healthcare Solutions - Medical Tourism Magazine - February 20th, 2024
- Clarifying Memory Loss Treatments: The Role of Stem Cells - Medical Tourism Magazine - February 20th, 2024
- Battling Inflammation: Stem Cell Therapy for Rheumatoid Arthritis - Medical Tourism Magazine - February 20th, 2024
- Digestive Health and Stem Cells: Treating Ulcerative Colitis and Crohn's Disease - Medical Tourism Magazine - February 20th, 2024
- Top Stem Cell Clinics in the USA: Pioneering Treatments for Chronic Conditions - Medical Tourism Magazine - February 20th, 2024
- Stem Cells and Autism: Understanding the Potential for Innovative Treatments - Medical Tourism Magazine - February 20th, 2024
- Stopping the awakening of sleeping Acute Myeloid Leukaemia stem cells to prevent disease relapse - University of Birmingham - February 20th, 2024
- City of Hope Achieves Ground Breaking Treatment for Blood Cancer and HIV - Medriva - February 18th, 2024
- Regenerative Medicine Market Size to Worth USD 95 Billion by 2032 - InvestorsObserver - February 18th, 2024
- North America Organoids Market Projected to Reach US$ 5.35 Billion by 2030, Riding on a CAGR of 21.5% - GlobeNewswire - February 18th, 2024
- Chinese team tests lung treatment that may be first to reverse COPD damage - South China Morning Post - February 15th, 2024
- Why leukemic stem cells not harmed by chemotherapy begin to grow and produce AML cells after treatment - Medical Xpress - February 15th, 2024
- Regenerative Medicine Market is Expected to Reach $49.0 Billion | MarketsandMarkets - Yahoo Finance - February 15th, 2024
- Study finds interleukin-24 enhances CAR-T cell therapy's effectiveness against cancer stem cells - News-Medical.Net - February 15th, 2024
- Oldest Patient 'Cured' of HIV Still in Remission 5 Years After Transplant for AML - Medpage Today - February 15th, 2024
- Drug used for cocaine addiction may pave way for new treatment of advanced colon cancer - EurekAlert - February 15th, 2024
- Hematopoietic Stem Cells and Their Role in Development and Disease Therapy - The Scientist - February 15th, 2024
- Biomedical Researcher Seeks to Improve Outcomes in Stem Cell Treatments - University of Arkansas Newswire - February 13th, 2024
- Top 3 grants in regenerative medicine: January 2024 - RegMedNet - February 13th, 2024
- Scalise returning to Washington next week with cancer in complete remission - The Hill - February 13th, 2024
- Unlocking the power of stem cell therapy - Drug Target Review - February 9th, 2024
- Digging into the Dangers of Gene Therapy - The Medicine Maker - February 7th, 2024
- Treating and preventing abnormal heart beats with stem cell muscle grafts - Medical Xpress - February 7th, 2024
- Regeneration of the Retina Using Pluripotent Stem Cells: A Comprehensive Review - Cureus - February 3rd, 2024
- I thought I'll give it a chance - Liam Harrison reveals his thought process in getting crucial stem cell treatment - Sportskeeda - February 3rd, 2024
- Jennifer J. Raab named President and CEO of The New York Stem Cell Foundation - EurekAlert - February 3rd, 2024
- High-dose chemotherapy and autologous haematopoietic stem-cell transplantation in older, fit patients with primary ... - The Lancet - January 31st, 2024
- Houston regenerative medicine company to IPO, move toward more human trials - InnovationMap - January 31st, 2024
- New study on promising stem cell-based therapy for Crohn's disease - Medical Xpress - January 31st, 2024
- Exploring pharmacological, non-pharmacological, and stem cell therapies for treatment of autism spectrum disorders - News-Medical.Net - January 29th, 2024
- Stem cell study shows how gene activity modulates the amount of immune cell production in mice - Medical Xpress - January 26th, 2024
- Regenerative Medicine Market Set to Surge with 25.36% CAGR, Projected to Reach US$122.381 Billion by 2028 - GlobeNewswire - January 26th, 2024
- Global Graft Versus Host Disease (GvHD) Treatment Market Forecast, 2028: High Treatment Costs and Infection Risks ... - GlobeNewswire - January 26th, 2024
- Individualized dose of anti-thymocyte globulin based on weight and pre-transplantation lymphocyte counts in pediatric ... - Nature.com - January 22nd, 2024
- Can Stem Cells Improve Knee Pain or Are They A Waste of Money? - Bloomberg - January 22nd, 2024
- 1st-of-its-kind therapy blocks immune attack after stem-cell transplant - Livescience.com - January 20th, 2024
- The Stem Cell Renaissance: Innovations, Collaborations, and the... - MedTech Outlook - January 20th, 2024
- Stem cell-based therapy for ALS deemed safe in Phase 2 study - ALS News Today - January 20th, 2024
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