
Human heart muscle cells derived from triple-engineered stem cells that are “invisible” to the immune system. The red is troponin, a protein that participates in cardiac muscle contraction. The blue is the cell’s nucleus. Researchers hope cells like these will eventually be used to treat heart failure. Credit: Xiaomeng Hu.
Technique Prevents Transplant Rejection in the Lab, a Major Advance for Stem Cell Therapies
UC San Francisco scientists have used the CRISPR-Cas9 gene-editing system to create the first pluripotent stem cells that are functionally “invisible” to the immune system, a feat of biological engineering that, in laboratory studies, prevented rejection of stem cell transplants. Because these “universal” stem cells can be manufactured more efficiently than stem cells tailor-made for each patient – the individualized approach that dominated earlier efforts – they bring the promise of regenerative medicine a step closer to reality.
“Scientists often tout the therapeutic potential of pluripotent stem cells, which can mature into any adult tissue, but the immune system has been a major impediment to safe and effective stem cell therapies,” said Tobias Deuse, MD, the Julien I.E. Hoffman, MD, Endowed Chair in Cardiac Surgery at UCSF and lead author of the new study, published Feb. 18 in the journal Nature Biotechnology.
The immune system is unforgiving. It’s programmed to eradicate anything it perceives as alien, which protects the body against infectious agents and other invaders that could wreak havoc if given free rein. But this also means that transplanted organs, tissues or cells are seen as a potentially dangerous foreign incursion, which invariably provokes a vigorous immune response leading to transplant rejection. When this occurs, donor and recipient are said to be – in medical parlance – “histocompatibility mismatched.”
“We can administer drugs that suppress immune activity and make rejection less likely. Unfortunately, these immunosuppressants leave patients more susceptible to infection and cancer,” explained Professor of Surgery Sonja Schrepfer, MD, PhD, the study’s senior author and director of the UCSF Transplant and Stem Cell Immunobiology (TSI) Lab at the time of the study.
In the realm of stem cell transplants, scientists once thought the rejection problem was solved by induced pluripotent stem cells (iPSCs), which are created from fully-mature cells – like skin or fat cells – that are reprogrammed in ways that allow them to develop into any of the myriad cells that comprise the body’s tissues and organs. If cells derived from iPSCs were transplanted into the same patient who donated the original cells, the thinking went, the body would see the transplanted cells as “self,” and would not mount an immune attack.
But in practice, clinical use of iPSCs has proven difficult. For reasons not yet understood, many patients’ cells prove unreceptive to reprogramming. Plus, it’s expensive and time-consuming to produce iPSCs for every patient who would benefit from stem cell therapy.
“There are many issues with iPSC technology, but the biggest hurdles are quality control and reproducibility. We don’t know what makes some cells amenable to reprogramming, but most scientists agree it can’t yet be reliably done,” Deuse said. “Most approaches to individualized iPSC therapies have been abandoned because of this.”
Deuse and Schrepfer wondered whether it might be possible to sidestep these challenges by creating “universal” iPSCs that could be used in any patient who needed them. In their new paper, they describe how after the activity of just three genes was altered, iPSCs were able to avoid rejection after being transplanted into histocompatibility-mismatched recipients with fully functional immune systems.
“This is the first time anyone has engineered cells that can be universally transplanted and can survive in immunocompetent recipients without eliciting an immune response,” Deuse said.
The researchers first used CRISPR to delete two genes that are essential for the proper functioning of a family of proteins known as major histocompatibility complex (MHC) class I and II. MHC proteins sit on the surface of almost all cells and display molecular signals that help the immune system distinguish an interloper from a native. Cells that are missing MHC genes don’t present these signals, so they don’t register as foreign. However, cells that are missing MHC proteins become targets of immune cells known as natural killer (NK) cells.
Working with professor Lewis Lanier, PhD – study co-author, chair of UCSF’s Department of Microbiology and Immunology, and an expert in the signals that activate and inhibit NK cell activity – Schrepfer’s team found that CD47, a cell surface protein that acts as a “do not eat me” signal against immune cells called macrophages, also has a strong inhibitory effect on NK cells.
Believing that CD47 might hold the key to completely shutting down rejection, the researchers loaded the CD47 gene into a virus, which delivered extra copies of the gene into mouse and human stem cells in which the MHC proteins had been knocked out.
CD47 indeed proved to be the missing piece of the puzzle. When the researchers transplanted their triple-engineered mouse stem cells into mismatched mice with normal immune systems, they observed no rejection. They then transplanted similarly engineered human stem cells into so-called humanized mice – mice whose immune systems have been replaced with components of the human immune system to mimic human immunity – and once again observed no rejection.
Additionally, the researchers derived various types of human heart cells from these triple-engineered stem cells, which they again transplanted into humanized mice. The stem cell-derived cardiac cells were able to achieve long-term survival and even began forming rudimentary blood vessels and heart muscle, raising the possibility that triple-engineered stem cells may one day be used to repair failing hearts.
“Our technique solves the problem of rejection of stem cells and stem cell-derived tissues, and represents a major advance for the stem cell therapy field,” Deuse said. “Our technique can benefit a wider range of people with production costs that are far lower than any individualized approach. We only need to manufacture our cells one time and we’re left with a product that can be applied universally.”
Learn more: CRISPR Gene Editing Makes Stem Cells ‘Invisible’ to Immune System
The Latest on: Stem cell transplants
via Google News
The Latest on: Stem cell transplants
- Sleights girl Evie Hodgson, 8, discharged from hospital after life-saving transplanton February 23, 2021 at 9:50 pm
An eight-year-old girl who has been given a second chance at life thanks to a life-saving transplant has been discharged from hospital. Evie Hodgson from Sleights, near Whitby, was diagnosed with ...
- Worldwide Industry for Cell Therapy Biomanufacturing to 2025 - Key Market Trends and Challengeson February 23, 2021 at 1:00 pm
Global Markets" report has been added to ResearchAndMarkets.com's offering. This research report presents an in-depth analysis of the global cell therapy biomanufacturing market by product type, ...
- Schiller Talks TKIs, Treatment Discontinuation, and Transplant in CMLon February 23, 2021 at 6:05 am
Gary J. Schiller, MD, discusses data from the 2020 ASH Annual Meeting and Exposition and the role of transplant in chronic myeloid leukemia.
- Scientists launch a pre-emptive strike on deadly post-transplant infectionon February 22, 2021 at 12:00 pm
A potential new treatment to protect immunosuppressed patients from human cytomegalovirus (HCMV) has been discovered by scientists at the University of Cambridge. Their study shows that certain ...
- Autologous Stem Cell and Non-Stem Cell Based Therapies Market Research Report by Manufacturers, Region, Type and Application, Forecast to 2026on February 22, 2021 at 5:08 am
Feb (Heraldkeepers) -- Autologous stem-cell transplantation (also called autogenetic, autogenic, or autogenic stem-cell transplantation or ...
- A Fort McKay family's Canada-wide search for stem cellson February 20, 2021 at 6:32 am
Ameilia Powder is a 10-year-old girl from First McKay Nation who is looking for a stem cell donor in order to recieve a bone marrow transplant.
- The impact of graft cell source on bloodstream infection in the first 100 days after allogeneic hematopoietic cell transplantationon February 19, 2021 at 10:09 am
Bloodstream infection (BSI) is a major infectious complication after allogeneic hematopoietic cell transplantation (HCT). To clarify the impact of graft cell source on the incidence of BSI after ...
- Off-the-Shelf NK Immunotherapy With Chemotherapy and Transplant Shows Early Activity in B-Cell NHLon February 17, 2021 at 7:02 am
Cord blood–derived natural killer immunotherapy, when paired with high-dose chemotherapy and autologous stem cell transplant, showcased early antitumor activity in patients with B-cell non-Hodgkin ...
- Associating Baseline PROs and Complications of Stem Cell Transplanton February 16, 2021 at 11:30 am
Thank you so much for the chance to talk a little bit about our work, looking at baseline patient-reported outcomes and their association with complications of hematopoietic stem cell transplant or ...
- Global Hematopoietic Stem Cell Transplantation (HSCT) Market to surpass US$ 4,391.0 million by 2027, Says Coherent Market Insights (CMI)on February 12, 2021 at 6:20 am
North America is projected to be the most lucrative region in the hematopoietic stem cell transplantation market due to rise in demands.
via Bing News