This article is 100% hardcore- rather technical, so really for the happy few with ambitions to understand all that jazz. On the other hand, the introduction and its message is provided in the first half, which is really very simple- i.e. fact is, that Cytori management has regarded its shareholders as "dumbo´s" for many years. Has deceived them with "simplicity", keyword- "ischemia or bloodflow", which in itself is totally off-base in respect of the potency of the cell-mix. In the mean time having private investigators unfold and PROVE the gigantic potential of the Gemisch (German: mix), which gemisch can do so much more and really possess a significant ability to regulate the immune system and combat inflammation.. The "solely ischemic" strategy brought the Company on the edge of financial collaps at several occasions in the past, due to concentration of efforts in CHF, which is very expensive per patient and which patients are already severely weakened by toxic conventional medicines, which focus resulted in heavy dilution, since they were "smelling the inflection point", instead of selecting the appropriate disorder fitting to the technology. And I guess everybody understands that.
First- a big thank you to our Greek friend John Gerondis, for finding the Aussie Cytori brochure, which opened my eyes, since finally Cytori disclosed for the first time ever really, what the mechanisms of therapeutic action of ADRCs are likely to be for the several applications discussed in the brochure. They are multi-facetted and confirmed my
understanding of the power of ADRCs- as stated above- this has NEVER EVER been disclosed by Cytori before.
Second- an introduction to a substancial factual virtue of ADRCs explained by Neil Riordan, owner of Cellmedicine and a scientist that shares his knowledge freely with the public in peer reviewed scientific papers and videos like the one here. He conducts -all in my view- the "practice of medicine" outside US borders in a responsible way, which the FDA I believe should allow -all practioners in the US with minimally manipulated cells.
Anyway- the take away messages from this video are (and proven by results in patients):
1. MSCs from fat INHIBIT the clonal expansion of activated T-cells that attack the bodies immune system.
2. Fat Tregs- or T regulatory cells, are extremely potent compared to their counterparts from other tissues and actually SUPPRESS activated T cells, i.e. help the body recover from "misguided" attacks by ones own cells to the immune system.
Both mechanisms of action of these parts of the "gimish" are SYSTEMIC in nature and just the fact that Cytori treated patients (and has approval for) with fistulae after Crohn´s- which is an autoimmune disorder- wouldnt quite guide an investor to "understanding" that ADRCs could help in autoimmune, since the fistulae tend to be treated "LOCALIZED" and are closing mainly due to the anti-inflammatory mechanisms.
Things look differently when an investor picks up from some source that SCLERODERMA is under "clinical investigation". For information what this disorder is all about you can visit my other site- cell-treatment.net . Remains to be said that Scleroderma is an immune disorder, which is virtually an unmet need and basically require SYSTEMIC treatment and upon inquiry one officially is being told "an academic customer is considering a trial to treat the degenerative soft tissue effects for scleroderma"
My ass- the usual smoke-screen. In my humble opinion the potential of ADRCs in treating autoimmune and neurological disorders will pale the cardiac opportunity, which in itself is gigantic, but the Company refuses to disclose all relevant information around this potential!!!
To give an idea of powers of the "gimish",which is fueled by cells, which behave like a potent cytokine factory- just an overview of the apps under clinical investigation and their most likely mechanisms of therapeutic action, which we havent been told about (at least not since the lid went on the IR information box on PI clinics back in late 2009)-
cardiac- yes mainly bloodflow, but in acute certainly anti-apoptotic and in case required anti-inflammatory as well.
liver- mainly immunomodulation (no bloodflow as suggested) probably even the immune stimulation type combatting infections, thereto trans- differentiation
acute renal- mainly anti-inflammatory, anti-apoptotic and mitogenic
stroke and neural repair- bloodflow, anti-apoptotic and trans-differentiation
but really key to this all- many auto-immune (and metabolic) disorders are key candidates for treatment with ADRCs and provide a huge potential sofar not conveyed or reported upon by Cytori, through immunomodulation and immune suppression made possible by extremely high (immuno-suppresive) IL-10 cytokines production by Tregs in the gimish.
Anyway- I guess you got the drift- the last mention in the quotation- being key to this all- requires some further explanation- not the virtue of MSC´s, since they seem to be clear- no the fact that Tregs are abundant in fat is absolute key to their future success and stand-alone ranking for ADRCs in the future of regenerative medicine- its getting to be a little techical know- so one can tune out here.
The scientific evidence of the Fat Treg potency
The basis is a study performed by a group of scientists from Harvard led by Diane Mathis (picture), which group published a paper in 2009, called-
Fat Treg cells: a liaison between the immune and metabolic systems
The abstract read as follows:
Obesity is accompanied by chronic, low-grade inflammation of adipose tissue, which promotes insulin resistance and type-2 diabetes. How does fat inflammation escape the powerful armamentarium of cells and molecules normally responsible for guarding against a run-away immune response? Regulatory CD4+ T cells expressing the transcription factor Foxp3 (termed Treg cells) are a lymphocyte lineage specialized in controlling immunologic reactivity. Treg cells with a unique phenotype were highly enriched in the abdominal fat of normal mice, but were strikingly and specifically reduced at this site in insulin-resistant models of obesity. In loss-offunction and gain-of-function experiments, Treg cells regulated the inflammatory state of adipose tissue and insulin resistance. Cytokines differentially synthesized by fat-resident regulatory and conventional T cells directly impacted on the synthesis of inflammatory mediators and glucose uptake by cultured adipocytes. These findings open the door to harnessing the anti-inflammatory properties of Treg cells to inhibit elements of the metabolic syndrome.
That sounds nice of course- it appears that these Tregs could help mankind in finding a solution for Diabetes Type 2, which she also mentions in the paper- We estimate that 15,000–20,000 Foxp3+ cells reside in one gram of epididymal adipose tissue in an ~30-week-old B6 mouse. Given their known potency, this value very likely represents a biologically significant number – for example, transferring as few as 5,000–10,000 Treg cells can protect a mouse from autoimmune diabetes (and many of the cells do not even survive the transfer process)
You can download the paper here: mathis- tregs-liaison_between_ immuneandmetabolic_systems.pdf1.92 MB02/05/2012, 21:44
However Dr. Thomas Ichim of MediStem interprets its findings from a different perspective, which at present should interest us slightly more- and th
at is its relevance towards combatting auto-immune disorders. His interpretation you can find in the following video, but before viewing I would suggest you take note of the description by Mathis et al of a Treg- the video and the following is all about (CD4+) Foxp3+ cells- so take note of this first-
A small subset of T lymphocytes, normally constituting only 5–20% of the CD4+ compartment, Treg cells are thought to be one of the body’s most critical defenses against inappropriate immune responses – operating in contexts of autoimmunity, allergy, inflammation, infection and tumorigenesis 13, 14. Typically, they control the behavior of other T cell populations, but can also influence the activities of innate immune system cells 15–17. Treg cells are quite specifically characterized by high-level expression of the forkhead/winged-helix transcription factor, Foxp3.
Summarizing the statements from the video:
- The T-regulatory (Treg) cells in adipose tissue are presently captured in the tissue itself and while captured inhibited to carry out their function in inhibiting activated T-cells because of leptin. So they need to be taken out of the adipose tissue, i.e. extracted, so they can perform their therapeutic work.
- The study by Diane Mathis´ group revealed that their is a much higher concentration of Fox3P+ cells- which are Tregs-(as part of the CD4 signaling population) in adipose tissue compared to other sources like Bone Marrow, Spleen, Lung etc.
- Tests by this group have shown that yes, these Fox3P+ cells do their job in inhibiting activated prolifirating T-cells.
- When looking at the cytokine level - the gene level showed much higher levels of Interleukin-10 (IL-10) than similar cells from other sources
- Same for the protein level, where a much higher concentration and production of IL-10 is seen.
The pictures in support of those statements (taken from the Mathis study can be viewed here-
The last two pictures (for me) the most relevant- Fat Tregs produce- when activated- enormous numbers of IL-10 cytokines, which one can read in many papers, have a profound impact on regulating immune disorders like Crohn´s, Rheumatoid Arthritis and probably MS.
I guess this proves the point I am making sufficiently and the Cytori scientists obviously know this too- at the only competing ADRC outfit on this globe- Cellerix (sub of Tigenix) a seperate Treg development department even exists.
In the Mathis study the proliferation of fat Tregs is mainly compared to the Lymph nodes and Spleen. The lymph nodes are organs which are part of the immune system and one would suspect the highest concentration of Tregs there. Spleen as storage organ- similar.
Cytori extracts the "gimish" from subcuteneous fat, which is the outer layer of the belly and not abdominal fat. The number of Tregs there are similar to LN, but their potency seems similar as in abdominal fat.