The main objective for a successful cell therapy treatment is to show a significant improvement as compared to the standard treatment regimen.  This is actually a key decision point the FDA uses in consideration of approving a therapy.  A given cell therapy from a biological perspective may in fact work, but it could be more expensive or less effective than the standard treatment.  If this is the case, then it would be a large uphill battle to justify its clinical application.

The principal question that clinicians, scientists, regulators, and the general public is asking is: what are the cells actually doing?   Each group in the above parties is very interested in the question, since it would provide an understanding of how the cells function.  Clinicians are interested on how the cells can modulate a disease or contribute to a cure.  Scientists are interested in the mechanisms on how the stem cells undertake their regenerative traits.  Regulators are interested in the safety and effectiveness of cell therapies.  Whereas the general public want reliable, easy to digest information about the general features of therapies and how they could be useful for treating diseases.

Although there is no absolute confirmation on what stem cells actually do, there has been a lot of research in this area with substantial data.  The potentially confusing inkling here is that different types of stem cells used for therapy may have different mechanisms of action.  For example, CD34 hematopoietic stem cells would be have much differently than, say neuronal stem cells.  This may feel quite obvious, but it has to be recognized that different cells have different mechanisms and could be used for different applications.

Today’s blog will focus on adipose MSCs and their apparent interactions. Overall, there are five generally agreed upon mechanisms of integration which have been reported for adipose MSCs.

1 – Trophic Support. MSCs release several factors and cytokines which support resident cells and they respond to an injury or tissue damage.  –These growth factors are secreted by MSCs support cell survival and contribute to wound healing.  Other cellular activities include complex mechanisms such as anti-scarring, angiogenesis, anti-apoptosis, nascent stem cell recruitment and cellular growth (1). A couple of interesting cases of MSC trophic support are described with the use of islet survival and function after transplantation and for neurodegenerative diseases (2, 3)

2 – Anti-Inflammatory. In line to trophic support, MSCs secrete cytokines which are anti-inflammatory in nature which help to balance production of inflammation brought on by T cells.  The immunosuppressive effects mediated by MSCs mainly involve interactions with T cells. When T cells are activated, they secrete pro-inflammatory cytokines such as TNF-α, IFN-γ, and IL-12. MSCs have shown the ability to inhibit the secretion of TNF-α, IFN-γ, and IL-12, mediated by the type 1 helper T cell pathway.  (4, 5)

3 – Differentiation into tissue. The hope and promise of stem cells center on their potential capability of differentiating into many different types of tissues.  This particular function for the stem cells is quite significant and requires strong evidence that this process actually occurs, in vivo.  In an in vitro system, mesenchymal stem cells from adipose tissue in particular differentiate into chondrocytes (cartilage cells), osteocytes (bone cells) and adipocytes (fat cells).  In fact, the International Society for Cell Therapy (ISCT) uses trilineage differentiation as a characteristic of human MSCs.  The same criteria may be applied to growing and testing MSCs from any animal In an in vivo system, the task is challenging to provide evidence to the scientific community regarding differentiation.   To do this successfully depends on the ability to monitor transplanted cells over a long period of time.

4 –MSC homing to an injury site. MSCs are capable of locating injured sites by homing to them. However, the dynamics and molecular mechanisms of MSCs trafficking to sites of injury have not been fully described.  The therapeutic delivery of MSCs is typically performed via intravenous systemic injection into a major vessel. Some time is required to allow the MSCs to home and engraft within sites of injury.  Not all the MSCs will actually end up at the injury site.  Initially, intravenous injected MSCs are rapidly cleared from the circulation and become entrapped within the lungs. After 1–5 days post injection, MSCs begin to exit the lungs and are found within the liver, spleen, kidneys, and bone marrow.

The apprehension with this feature is the MSCs do have the inherent ability to migrate.  Although most of the MSCs will home into a site of injury, a large proportion of them will migrate to other tissues.  An example of this was noted in dogs where repeated injections into the periocular and intra-articular regions showed migration and subsequent engraftment of MSCs in the thymus as well as the gastrointestinal tract. (6)  Although in this situation the migrating MSCs did not contribute to any harm, some regulatory agencies could cite this as a safety concern.  The burden of proof to show that the cells will not harm the patient is a difficult task and tends to require large clinical trials and an exhausting cell tracking long term study.  As this group showed, after two weeks post injection, the MSCs were able to deliver favorable immunomodulatory support and demonstrated the potential for a therapeutic benefit using MSCs.

5 – Immune system modulation. The most anticipated function of stem cells and widely studied are the effects that these cells have on the immune system. An immunomodulatory effect is well described with treatments which involve MSCs. This effect can be broad, from direct inhibition of lymphocyte proliferation, induction of regulatory T and B cells, to resetting the immune system. Although MSCs are not part of the immune system according to the established definitions (7), they interact with all immune cell types. They secrete a large range of anti-inflammatory as well as pro-inflammatory factors, among them cytokines, chemokines and prostaglandins, which target immune cells and affect their function. (8) In addition to paracrine interactions, MSCs express cell surface molecules that undergo interaction with various immune cells. The expression of certain adhesion markers, such as ICAM-1, increase the recruitment of activated immune cells to allow the immune cells to interact with the MSCs (9).

The current hypothesis for cell therapy is that the therapeutic cells can either progress in these possible pathways: (a) the injected cells home towards the damaged area, differentiate into several cell types and actively regenerate the damaged tissue, or (b) the injected cells respond to signaling factors, such as cytokines or cell to cell interactions, and behave in a paracrine support role to reduce inflammation and allow resident cells to repair the damaged area.  A third scenario could include a combination of both pathways to some extent.

The first scenario is in line to what regenerative medicine is all about.  Even though this mechanism is not fully defined, some of the recent data support the notion of MSCs secrete cytokines and contribute to lowering levels in inflammation.(10, 11) The idea here Is that the MSCs are able to home into the damaged areas and integrate into the area to some extent.

If cell therapy is to be fully and officially adopted, more data is needed to show what the cells do after they are administered.  The other substantial component to figuring out how MSCs work is their localization patterns. The mechanism of the cells would be an intense exercise in some type of cell tracking experiments.

References:

  1. Caplan A, J. et al., Cell. Biochem. 98: 1076–1084, 2006
  2. Joyce N, et al., Regenerative Medicine, Vol. 5, No. 6, Pages 933-946, Nov 2010
  3. Park, K, et al., Transplantation, Vol 89 – Issue 5 – pp 509-517, Mar 2010
  4. Abreu S, et al, A109. REMODELING AND THE MATRIX. May 1, 2016, A2828-A2828
  5. Manning C, et al, Stem Cell Research & Therapy20156:74
  6. Wood A, et al, Journal of Ocular Pharmacology and Therapeutics. June 2012, 28(3): 307-317.
  7. Hoogduijn MJ. Arthritis Res Ther (2015) 17(1):88.
  8. Soleymaninejadian E, et al., Am J Reprod Immunol (2012) 67(1):1–8
  9. Augello A, et al., Eur J Immunol (2005) 35(5):1482–90
  10. Yanez R, et al, Stem Cells, 24, (11), P 2582–2591, Nov 2006
  11. Jung W, et al, Tissue and Cell, 47, (1), P 86–93 Feb 2015

 

 

 

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