Fujifilm Succeeds in Substantially Boosting the Anti-inflammatory Effect of Mesenchymal Stem Cells

CELLNEST, an extracellular matrix suitable for cell culture, enhances the effectiveness of treatment
— Epoch-making research outcome in the field of regenerative medicine

March 8, 2017

FUJIFILM Corporation (President: Kenji Sukeno) has succeeded in substantially boosting the anti-inflammatory effect of mesenchymal stem cells (MSC)* by combining the cells with an extracellular matrix suitable for cell culture.
The extracellular matrix is a set of proteins such as collagens which are found on the outside of cells. They support the organism's tissues, while also playing an important role in regulating cell replication and division. Tapping into collagen technologies and genetic engineering technologies nurtured through photographic film research over many years, Fujifilm has developed and launched CELLNEST™ Recombinant Peptide based on Human Collagen Type I** (hereinafter “Cellnest”,) an extracellular matrix which does not contain any animal-derived ingredient and thus achieving a high level of safety and biological compatibility. Utilizing Cellnest, Fujifilm has made the following research achievements.

Research Achievements

1) It has been verified that the 3D cell structure “CellSaic”*** (Figure 2), which combines MSC and Cellnest's petaloid μ-pieces (Figure 1), triples or even quadruples the secretion of anti-inflammatory humoral factors*4, which MSC produces in response to inflammatory irritation.
2) The research has confirmed that the administration of CellSaic on mouse models of inflammatory bowel disease reduces inflammation and promotes tissue regeneration in the large intestine.

This is an epoch-making finding that could dramatically increase MSC's anti-inflammatory effect and enable the regeneration of various tissues.

[Figure1]Cellnest's petaloid μ-pieces / [Figure2]3D cell structure “CellSaic”

[Research background]

Regenerative medicine is a new medical technology for regenerating damaged organs and tissues and restoring their functions. Treatment using MSC in particular is attracting attention for its biological safety and confirmed effectiveness on a range of conditions including inflammation, cerebral infarction and cartilage injury. MSC is believed to deliver composite effects by secreting humoral factors and attaching itself to cells to initiate reactions. However, treatment with MSC alone has resulted in varied or insufficient effectiveness.
Fujifilm developed petaloid μ-pieces of the safe extracellular matrix “Cellnest,” which does not contain any animal-derived ingredients, and combined it with cells to produce “CellSaic” for boosting the effectiveness of cell therapy. In a pancreatic islet transplantation test using mouse models for diabetes, CellSaic substantially increased the cell engraftment rate, and successfully lowered blood glucose levels to normal levels, verifying its effect of enhanced treatment effectiveness in cell transplantation.
In the latest achievement, Fujifilm has researched how CellSaic can be used to enhance the effectiveness of inflammatory disease treatment involving MSC, and produced the following results:

[Test results 1] Verifying that the secretion of anti-inflammatory humoral factor TSG-6*5, generated by MSC in response to inflammatory irritation, is tripled / quadrupled

(1) Test description

The test prepared samples in an MSC-only group and an MSC – CellSaic combination group, using two types of MSC, one derived from human fat and the other derived from bone marrow. They were further divided into a group with added inflammation factor TNFα*6 and a group with no added TNFα. The samples were cultured for 48 hours, before the secreted amount of the anti-inflammatory humoral factor TSG-6 was compared.

(2) Test results

In the group of samples to which TNFα was added, samples cultured with CellSaic showed, compared to those cultured with MSC only, three-times greater secretion of TSG-6 for MSC derived from human fat and four-times greater secretion of TSG-6 for MSC derived from bone marrow.

[Figure3]Comparison in the secretion amount of anti-inflammatory humoral factor TSG-6

[Test results 2] Reducing inflammation, improving symptoms, (such as weight loss) and promoting tissue regeneration in the large intestine in a test on mouse models of inflammatory bowel disease

(1) Test description

Mouse models of inflammatory bowel disease were prepared by administering the inflammation-inducing agent dextran sulfate sodium (DSS) to the mice for seven days. Samples from the group given human fat-derived MSC only, the group given MSC formulated into CellSaic (CellSaic group) and the control group which did not receive any MSC, were compared with regard to the level of improvement in typical symptoms of inflammatory bowel disease, such as weight loss and bowel shortening. MSC / CellSaic was administered by subcutaneous injection on Day 7 of the test.

(2) Test results

Compared to the control group, the CellSaic group showed recovery from weight loss and significant regeneration of tissues in the large intestine. The level of recovery was greater even in comparison with the MSC-only group.
The results indicate that, compared to MSC-only treatment, the use of CellSaic results in the secretion of a greater amount of anti-inflammatory humoral factors in response to inflammation and the achievement of a greater anti-inflammatory effect in vivo, thereby boosting the effectiveness of the treatment.

[Figure4]Comparison of weight transition (left) and length of the large intestine (right) in mouse models of inflammatory bowel disease

These results suggest that CellSaic, which combines Cellnest's petaloid μ-pieces with cells, can be applied to a range of regenerative medicine treatments including cell transplantation and tissue regeneration. The results will be presented at the 16th Congress of the Japanese Society for Regenerative Medicine, to be held at the Sendai International Center on March 8, 2017.

Fujifilm will continue to further promote R&D in the field of regenerative medicine and contribute to its industrialization by tapping into the high-functional material technologies and engineering technologies fostered through photographic film research over many years, and combining these technologies with the technologies developed by regenerative medicine affiliates, including the world-leading iPS cell technologies and know-how of Cellular Dynamics International Inc. and technologies for the production of cells for use in treatment developed by Japan Tissue Engineering Co., Ltd.

  • * Mesenchymal stem cells are somatic stem cells of the mesenchymal system (including bone cells, cartilage cells, tendon cells, fat cells). They have differentiation potency mainly towards mesenchymal cells, and are considered to have a strong potential as a cell source for various forms of regenerative medicine.
  • ** CELLNEST™ Recombinant Peptide based on Human Collagen Type I is an artificial protein produced with yeast t cells using genetic engineering. It was launched in December 2014 as a reagent for use in research. Collagen is a major protein making up connective tissues in animals. Human collagen type I is found in the bones and the skin, accounting for 95% of all collagen in human beings.
  • *** CellSaic is a 3D mosaic cell structure, combining cells and the extracellular matrix. CellSaic is a term coined from “Cell and Scaffold forming Mosaic,” combining “cell” and “-saic” from the word “mosaic.”
  • *4 Humoral factors are proteins secreted by cells, conveying signals between cells. Many play a role in the immune system and inflammation.
  • *5 Tumor necrosis factor stimulated gene 6 is a multifunctional protein associated with inflammation. It is known to have an anti-inflammatory effect.
  • *6 Tumor necrosis factor is a type of humoral factor. It is thought to be one of the main causes of inflammation. TNFα signaling increases the production of inflammatory humoral factors.

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