'Stealthy' stem cells better for treating tendon injuries in horses

February 04, 2021

Treating equine donor stem cells with a growth factor called TGF-β2 may allow them to avoid "tripping" the immune response in recipients, according to new research from North Carolina State University. The work could simplify the stem cell treatment process for ligament and tendon injuries in horses, and may also have implications for human stem cell therapies.

Mesenchymal stem cell therapy is a promising avenue for treating musculoskeletal injuries - particularly tendon and ligament injuries - in horses. Mesenchymal stem cells are adult stem cells found in bone marrow that act as repair directors, producing secretions that recruit paracrine, or healing, factors to the site of injury.

Just as blood cells have "types," depending upon which antigens are on the blood cell's surface, mesenchymal stem cells have differing sets of major histocompatibility complex molecules, or MHCs, on their surfaces. If the MHCs of donor and recipient aren't a match, the donor's stem cells cause an immune response. In organ transplants, MHCs are carefully matched to prevent rejection.

"These treatments aren't like a bone marrow transplant or an organ transplant," says Lauren Schnabel, associate professor of equine orthopedic surgery at NC State and corresponding author of the work. "Since the mesenchymal stem cells are being used temporarily to treat localized injury, researchers once thought that they didn't need to be matched - that they wouldn't cause an immune response. Unfortunately, that isn't the case."

Schnabel and Alix Berglund, a research scholar at NC State and lead author of the paper describing the work, wanted to find a way to utilize mesenchymal stem cell therapy without the time, effort and additional cost of donor/recipient matching.

"Since these cells don't have to be in the body as long as an organ does, 'hiding' them from the immune system long enough for them to secrete their paracrine factors could be a way around donor/recipient matching," Berglund says. "Downregulating expression of the MHC molecules could be one way to do this."

The researchers cultured stem cells and lymphocytes, or T cells, from eight horses, cross-pairing them in vitro so that the stem cells and lymphocytes had differing MHC haplotypes. In one group, stem cells had been treated with transforming growth factor beta (TGF-β2) prior to being added to the lymphocytes in the culture media; the other group was untreated. TGF-β2 is a cell-signaling molecule produced by white blood cells that blocks immune responses.

Cultures with treated stem cells had a 50% higher stem cell survival rate than untreated cultures.

"We use mesenchymal stem cells to treat musculoskeletal injuries - particularly tendon injuries - in horses very effectively," Schnabel says. "And while you can extract the secretions from the stem cells, you get better results with the cells themselves. Stem cells aren't just a reservoir of secretions, they're a communications hub that tells other cells what they should be doing. So finding a way to utilize these cells without stimulating immune response gives us better treatment options."

"This is a promising pilot study," Berglund says. "Our next steps will be to further explore the immune response in vivo, and to look at human cells in vitro, as this work has excellent potential to help humans with these injuries as well."

The research appears in Frontiers in Cell and Developmental Biology, and was supported by the National Institutes of Health (grants K08AR060875 and K01OD027037) and the Morris Animal Foundation (grants D16EQ-405 and D18EQ-055). Research specialist Julie Long and statistician James Robertson, both of NC State, also contributed to the work.
-end-
Note to editors: An abstract follows.

"TGF-b2 Reduces the Cell-Mediated Immunogenicity of Equine MHC-Mismatched Bone Marrow-Derived Mesenchymal Stem Cells Without Altering Immunomodulatory Properties"

DOI: 10.3389/fcell.2021.628382

Authors: Alix K. Berglund, Julie M. Long, James B. Robertson, Lauren V. Schnabel, North Carolina State University

Published: Feb. 4, 2021 in Frontiers in Cell and Developmental Biology

Abstract: Allogeneic mesenchymal stem cells (MSCs) are a promising cell therapy for treating numerous diseases, but major histocompatibility complex (MHC)-mismatched MSCs can be rejected by the recipient's immune system. Pre-treating MSCs with transforming growth factor-b2 (TGF-b2) to downregulate surface expression of MHC molecules may enhance the ability of allogeneic MSCs to evade immune responses. We used lymphocyte proliferation assays and ELISAs to analyze the immunomodulatory potential of TGF-b2-treated equine bone marrow-derived MSCs. T cell activation and cytotoxicity assays were then used to measure the in vitro cell-mediated immunogenicity. Similar to untreated MSCs, TGF-b2-treated MSCs inhibited T cell proliferation and did not stimulate MHC-mismatched T cells to proliferate. Additionally, similar quantities of prostaglandin E2 and TGF-b1 were detected in assays with untreated and TGF-b2-treated MSCs supporting that TGF-b2-treated MSCs retain their strong immunomodulatory properties in vitro. Compared to untreated MSCs, TGF-b2-treated MSCs induced less T cell activation and had reduced cell-mediated cytotoxicity in vitro. These results indicate that treating MSCs with TGF-b2 is a promising strategy to reduce the cell-mediated immunogenicity of MHC-mismatched MSCs and facilitate allogeneic MSC therapy.

North Carolina State University

Related Stem Cells Articles from Brightsurf:

SUTD researchers create heart cells from stem cells using 3D printing
SUTD researchers 3D printed a micro-scaled physical device to demonstrate a new level of control in the directed differentiation of stem cells, enhancing the production of cardiomyocytes.

More selective elimination of leukemia stem cells and blood stem cells
Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia.

Computer simulations visualize how DNA is recognized to convert cells into stem cells
Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.

First events in stem cells becoming specialized cells needed for organ development
Cell biologists at the University of Toronto shed light on the very first step stem cells go through to turn into the specialized cells that make up organs.

Surprising research result: All immature cells can develop into stem cells
New sensational study conducted at the University of Copenhagen disproves traditional knowledge of stem cell development.

The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.

Healthy blood stem cells have as many DNA mutations as leukemic cells
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ.

New method grows brain cells from stem cells quickly and efficiently
Researchers at Lund University in Sweden have developed a faster method to generate functional brain cells, called astrocytes, from embryonic stem cells.

NUS researchers confine mature cells to turn them into stem cells
Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute at the National University of Singapore and the FIRC Institute of Molecular Oncology in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification -- by confining them to a defined geometric space for an extended period of time.

Researchers develop a new method for turning skin cells into pluripotent stem cells
Researchers at the University of Helsinki, Finland, and Karolinska Institutet, Sweden, have for the first time succeeded in converting human skin cells into pluripotent stem cells by activating the cell's own genes.

Read More: Stem Cells News and Stem Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.