Tag Archives: bone marrow stem cell cytokines

Safety and Efficacy Considerations of Stem Cell Technologies for Skin Care: : ADSCs preferred Over BMSCs

Mesenchymal Stem Cells and their Progenitor Cells (Fibroblasts) Derived from Skin are Superior to Bone Marrow Derived Mesenchymal Stem Cells

When addressing safety and efficacy concerns of stem cells, we must consider tissue-specific stem cells. Choosing the appropriate stem cell type to match the condition to be treated is critical not only to efficacy, but most importantly, safety of the therapeutic. Beyond the genetic and epigenetic factors that influence stem cell phenotype as embryonic stem cells differentiate into somatic stem cells, the immediate niche of the stem cell will have profound influence on the cell’s phenotype. Therefore, the appropriate use of adipose derived mesenchymal stem cells (ADSCs), and their related progenitor cells from the skin, fibroblasts, is optimal for skin care compared to bone marrow mesenchymal stem cells (BMSCs)

Let’s consider some of the problems BMSCs pose for developing skin care products. The complexity of the bone marrow (BM) niche can lead to many stem cell phenotypes, whether we consider hematopoietic stem cells (HSCs) or bone marrow mesenchymal stem cells (BMSCs). Here I will discuss the properties of BMSCs, not HSCs. Because of the complexity, many BMSC phenotypes exist, including disease causing phenotypes that are varied and hard to distinguish – a part of the problem in using BMSC for therapeutic development. This complication, unlike that for ADSCS, includes recirculated cells, particularly recirculated cancer cells. Once a tumor cell disseminates into the BM, the cancer cell often displays phenotypic characteristics of BMSCs rendering cancer cells difficult to distinguish from BMSCs. BM is a site of BMSCs that may differentiate into HSCs and recirculating blood cells that may differentiate into BMSCs [see Cardenas et al; Tondreau et al]. BMSCs are also found outside of the niche in peripheral blood and home into sites of injury and cancer tissue where they are educated into becoming a pro-cancerous phenotype. Recirculated melanoma and myelogenous leukemia cells in BM interact with BMSCs to change the phenotype of the BMSC to one that is cancer promoting by enhancing their proliferation, migration, and invasion and altering the production of proteins involved in the regulation of the cell cycle. Indeed, melanoma tumor cells start to disseminate to BM during the initial steps of tumor development. In breast cancer patients, detection of recirculated cancer cells that disseminated in BM predicts recurrence of the cancer. Cancer cells can fuse with BMSCs and change their phenotype, or release exosomes to change the phenotype of BMSCs to cancer promoting. Indeed breast tumor cells fuse spontaneously with bone marrow mesenchymal stem cells. This fusion may facilitate the exchange of cellular material from the cancer cell to the BMSC rendering the fused cell more oncogenic. Further, others have found the same result of this fusion and exchange of cellular material, which has been found to increase metastasis. For example, Li et al found that human hepatocellular carcinoma cells with a low metastatic potential exhibit a significantly increased metastatic potential following fusion with BMSCs in vitro and in xenograft studies. This means that the BMSCs and their molecules/exosomes, having been conditioned by tumor cells, were found to increase the probability of cancer in human patients. The various phenotypes of BMSCs, including the cancerous phenotypes are difficult to distinguish. In contrast, even ADSCs derived from cancer patients have been found to be safe for therapeutic development.

One of many reasons why ADSCs are preferred compared to BMSCs is that ADSCs express a low level of major histocompatibility complex (MHC) class I molecules and do not express MHC class II and costimulatory molecules. Even the exosomes of BMSCs express MHC class II proteins. These problems in BMSCs are amplified when using donor, allogeneic BMSCs that have been replicated many times, essentially aging the cells, during expansion to develop the therapeutic. This is in contradistinction to ADSCs. Critically, when comparing experimental data of BMSCs to ADSCs from the same human donor, “ADSCs have a “younger” phenotype,” according to stem cell scientists. Indeed, Burrow et al found that BMSCs have, among other negative attributes compared to ADSCs, an increased level of senescence compared to matched ADSCs. Senescent cells develop the senescence-associated secretory phenotype (SASP), a pro-inflammatory set of molecules where the local tissue effects of a SASP or specific SASP components have been found to be involved in a wide variety of age-related pathologies in vivo such as hyperplastic diseases, including cancer. Whereas the use of BMSC transplants has a history of medical adverse events, including the induction of cancer in the recipient (Maguire, 2019), fat grafting, along with its constituent ADSCs, have a long history of safety in medical procedures dating back to 1893 when the German surgeon Gustav Neuber transplanted adipose tissue from the arm to the orbit of the eye in an autologous procedure to fill the depressed space resulting from a postinfectious scar. Fat grafting’s long history of being safe, regardless of the harvesting techniques used in patients, has been recently reviewed by physician-scientists at Baylor College of Medicine. Furthermore, physician-scientists at Stanford University School of Medicine have recently reviewed the safety and efficacy of using ADSCs to augment the outcomes of autologous fat transfers. Scientists have found that ADSCs and fat grafting for treating breast cancer-related lymphedema is safe and efficacious during a one year follow-on, where patient-reported outcomes improved significantly with time. In a randomized, comparator-controlled, single-blind, parallel-group, multicenter study in which patients with diabetic foot ulcers were recruited consecutively from four centers, ADSCs in a hydrogel was compared to hydrogel control. Complete wound closure was achieved for 73% in the treatment group and 47% in the control group at week 8. Complete wound closure was achieved for 82% in the treatment group and 53% in the control group at week 12. The Kaplan–Meier (a non-parametric statistic used for small samples or for data without a normal distribution) median times to complete closure were 28.5 and 63.0 days for the treatment group and the control group, respectively. Treatment of patients undergoing radiotherapy with adult ADSCs from lipoaspirate were followed for 31 months and patients with “otherwise untreatable patients exhibiting initial irreversible functional damage” were found to have systematic improvement or remission of symptoms in all of those evaluated. In animal models with a full thickness skin wound, administration of ADSCs, either intravenously, intramuscularly, or topically, accelerates wound healing, with more rapid reepithelialization and increased granulation tissue formation, and topically applied the ADSCs improved skin wound healing by reducing inflammation through the induction of macrophage polarization from a pro-inflammatory (M1) to a pro-repair (M2) phenotype.

All in all, companies using BMSCs to develop their skin care products demonstrates a profound ignorance of the related science. Incompetence, and a greedy, lazy approach to serving the skin care market is demonstrated by those using bone marrow stem cells to develop skin care products that potentially damage their clients.

Procell Microneedling Device Injures Dermis and Epidermis, Inducing Adverse Events in its Users

I was recently asked to review a cosmetic microneedling device white paper, meaning not a peer-review publications, rather an internal document generated by a company for sales purposes, from a company in Texas called Procell. As I’ve reported previously in peer-reviewed, PubMed listed papers, microneedling is a deep wounding procedure that activates the innate and adaptive immune systems and induces a wounded-proliferative state in the skin that is inflammatory and possibly pro-oncogenic. Sadly, this company, with its medical director (Mitchel Schwartz), who has no peer-reviewed publications and is paying for this study, is selling this product online and apparently making illegal sales to estheticians in states where microneedling procedures performed on others by estheticians is illegal.

The study in question here was performed by a physician in Canada who has no peer-reviewed publications, and the study, and the physician performing the study, were paid by Procell. The Procell device uses an array of needles that are 250 micrometers in length, with the thickness of the needles not reported. The device is run over the face such that these needles are puncturing holes in the epidermis and dermis at high rates, thus injuring both the epidermis and dermis.

The study design and the results are indicative of an inexperienced practitioner performing a study. First, the author states, “This study is a prospective, evaluator-blinded, single-site study, involving up to 30
subjects comparing clinical benefits after a treatment series versus baseline.” The claim of “evaluator-blinded” is ridiculous. Each subject serves as her own control, with photos being taken before and after treatment, and its easy for the evaluator to know who they are analyzing. Then they have a section called, “3.5 Randomization of Subjects.’ There is no randomization of the subjects. All are given the treatment. Next they say that “Photographic assessments will be conducted by a blinded expect evaluator.” I think they meant “expert” instead of “expect.” Although I think “expect evaluator” is the better descriptor, I’ll give them the benefit of the doubt. Regardless, the evaluator can easily identify each patient through their photos, and know what picture has been captured before and after the procedure. This is all just gobbledygook, and is either a consequence of ineptitude and/or fraud.

There are no results presented in the paper, only a conclusion. Yes, that’s right. No results are presented. What they do present in their “Safety Analysis” is a set on incongruous statements about how one patient was injured. Here’s what they reported in their “Safety Analysis”:

8.0 Safety Analysis
8.1 Safety Results:
To assess safety, all subjects were evaluated for adverse events during treatment and at all follow up visits. There was one event reported during the study duration.
The subject reported a “break out” along her jawline, which was evaluated by the
Primary Investigator. The effects were mild and transient in nature. The event was
coded as “possibly related to the procedure”. Upon further investigation and follow up
by the Primary Investigator, the subject was determined to have a baseline condition,
which should have eliminated her from study inclusion. The Investigator’s notes and
letter to file are included in the dataset for reference. All other subjects treated were
evaluated and no other events were reported.

My comment: (here they’re saying one of the patients had an adverse reaction)

9.0 Deviations from CIP
Based on the Primary Investigator’s assessment of the subject who has a possible
related event, he has concluded that this subject should not have been included in the
study based on her underlying clinical condition of inflammatory rosacea.

My comment: (here they’re saying the physician screwed up and shouldn’t have included this patient in the study)

10.0. CONCLUSION
During the study, all subjects tolerated the treatment well demonstrating only mild
erythema which was aniticpated [sic]. Improvement in the overall aesthetic appearance of
the skin was reported across all independent evaluators. Based on the results of this
study the ProCell .25mm Microchanneling system is safe to be used across all skin
types and can offer improvement in overall skin appearance as reported by both
patient and Independent evaluators.

My Comment: (here they contradict themselves, saying that the procedure is good for all skin types)

Here’s an image from the study so you can see for yourself:

Combine this inflammatory-proliferative, injurious procedure with the bone marrow mesenchymal stem cell cytokines that they sell, and one has set themselves up for adverse events, possibly long-term. There are skin conditions for which microneedling, when not performed repeatedly, is beneficial and the benefits out way the risks. Acne scarring and other types of scars can be an example. To quell the inflammation associated with the procedure and to set the immune system into a anti-inflammatory, pro-repair state, use the S2RM technology, found to be safe and efficacious, contained in Neogenesis Recovery.

Why Skin-Derived, Adipose Mesenchymal Stem Cell Released Molecules (NeoGenesis) Are Better Than Bone Marrow Mesenchymal Stem Cell Cytokines (AnteAge) for Post-Procedure Healing

What AnteAge Doesn’t Know and Therefore Doesn’t Tell You

Consider the stem cells used by AnteAge to make their products: Bone Marrow Mesenchymal Stem Cells (BMSCs) and the molecules they release prolong and enhance inflammation by increasing survival and function of neutrophils (Castella et al, 2011). Under hypoxic conditions, which induces the activation of TRL4, BMSCs secrete pro-inflammatory factors and decrease the polarization of macrophages from the M1 to M2 phenotype (Faulknor et al, 2017; Waterman et al, 2010). Therefore, BMSCs cultured in normal hypoxic conditions in the laboratory are secreting pro-inflammatory factors and when administered to wounded skin will induce inflammation by recruiting neutrophils and M1 type pro-inflammatory macrophages. When you put AnteAge on your skin, these are the pro-inflammatory molecules damging your skin. In contradistinction, consider the cells used by Neogenesis. The phenotype and stem cell released molecules (also called the secretome) from skin-derived adipose mesenchymal stem cells (AMSCs) are largely unaffected by prolonged hypoxia, not recruiting neutrophils (Kalinina et al, 2015), and the molecules released from AMSCs were found to better induce the effects of the anti-inflammatory M2 macrophage phenotype than the molecules released from BMSCs (Sukho et al, 2018). These results provide strong evidence that the molecules released from AMSC are more beneficial than those from BMSCs to induce appropriate wound healing processes through the shift from a pro-inflammatory state to an anti-inflammatory, pro-healing state.

These pro-inflammatory signals from BMSC cytokines are in addition to their likelihood of containing pro-oncogenic signals that are absent in AMSCs, that I have previously reviewed in multiple, peer-reviewed, National Library of Medicine journal articles (Maguire, 2019; 2021; 2022).

Why does AnteAge use these inflammatory and potentially oncogenic molecules in their products? The first clue comes from who founded the company and was its CEO for years, John Sanderson. A former physician who lost his medical license because of incompetence, repeated incompetence, and sexual misconduct with one of his patients.

Sanderson previously was a family practice physician with an undergraduate medical degree – a bachelor’s degree in medicine. Once Sanderson finished his Canadian undergraduate degree in medicine, once he passed the medical board test in the US, regulations permitted him to use the designation “M.D.” Sanderson frequently finds himself in disputes with other companies, one of which exposed that Sanderson committed domestic violence. He was not trained as a dermatologist and was not board certified. He obviously has little to no understanding of the skin’s powerful immune system, and no idea of how bone marrow mesenchymal stem cells work in the body. Upon losing his medical license, he started a company to do further harm to people by having them use products that induce inflammation and potentially cancer.

Trying to understand why a company would bring a proinflammatory, possibly pro-oncogenic product to the market, I looked closer at the company. Because John Sanderson is not a scientist, and has never listed that he has any scientific publication, only misleading blogs, I wondered how did he come to choose his technology. I discovered that Sanderson had enlisted fellow Canadian, Jonathan Lakey, Ph.D. as his scientific advisor. To no surprise, the man who had lost his medical license because of incompetence had hired a scientist, Jonathan Lakey, who had been fired from his university because of fraud.

A non-profit government organization in Canada fired Jonathan Lakey for the same reason:

Then Jonathan Lakey was charged with fraud and racketeering at one of the companies in which he was an officer:

Jonathan Lakey’s involvement with a number of other companies that are pump and dump schemes has made the news a number of times. Clearly, using a product on your skin from this dynamic fraudster-incompetence duo is a bad choice – they do not have anyone’s well being in mind.

There are other skin care companies led by physicians. I suggest if you’re interested in their products, go to the state medical board website in which they practice, and look at the current status of their medical license. For example, you can search physicians in California here, and in Colorado here. You may be surprised what you find. Simply type in their name, and you’re likely to find disiplinery actions and loss of license.

References

Castella M.A. et al (2011) Toll-like receptor-3-activated human mesenchymal stromal cells significantly prolong the survival and function of neutrophils. Stem Cells. 29:1001–1011.

Faulknor R.A. et al (2017) Hypoxia impairs mesenchymal stromal cell-induced macrophage M1 to M2. Technology. 2017;5:81–86. doi: 10.1142/S2339547817500042.

Kalinina N. et al. (2015) Characterization of secretomes provides evidence for adipose-derived mesenchymal stromal cells subtypes. Stem Cell Res. Ther. ;6:221.

Maguire G. Transplanted stem cells survive a long time: do they make you sick? J R Soc Med. 2019 Oct;112(10):412-414.

Maguire G. (2021) Stem cells part of the innate and adaptive immune systems as a therapeutic for Covid-19. Commun Integr Biol. 14(1):186-198.

Maguire G. (2022) Chronic inflammation induced by microneedling and the use of bone marrow stem cell cytokines. J Tissue Viability. 31(4):687-692.

Sukho P et al (2018) Human mesenchymal stromal cell sheets induce macrophages predominantly to an anti-inflammatory phenotype. Stem Cells Dev. 27:922–934.

Waterman R.S. et al (2010) A new mesenchymal stem cell (MSC) paradigm, polarization into a pro-inflammatory MSC1 or an immunosuppressive MSC2 phenotype. PLoS ONE. 5:e10088.