Chronic inflammation induced by microneedling and the use of bone marrow stem cell cytokines.

Physicians advocating the frequent use of microneedling for skin care are advocating for a potentially dangerous procedure, especially when coupled with the topical application of bone marrow stem cell derived cytokines. Not only are the physicians who advocate for frequent microneedling as a skin care procedure not Board Certified in Dermatology (FAAD or FAOCD), they are not dermatologist; rather they are family practitioners. Further, they don't have M.D. or D.O. medical doctorate degrees, rather they have truncated bachelor in medicine degrees with limited education and training. Unlike board certified dermatologists, these physicians simply have neither a deep knowledge of dermatology, nor knowledge of the immunology of the skin. These physicians have developed and promulgated books, blogs, and training classes for these procedures that are offered to non-physicians, often to estheticians. Advocating the frequent use of microneedling for skin care, especially when coupled with the topical application of bone marrow stem cell derived cytokines induces a damaging chronic inflammatory state in the skin, and likely systemic inflammation too. Microneedling of the skin, even under sterile conditions, elicits a sterile inflammatory response, including early recruitment of neutrophils, throughout the layers of the skin, and even systemically. Given the non-sterile nature of the skin, a rich microbiome, including bacteria, viruses, and fungi, at the skin's surface, these procedures may allow microneedling to cause these microorganisms to gain entry into the epidermis and dermis, furthering an inflammatory response already induced by the wound and associated inflammatogenic self-molecules. The use of bone marrow stem cell cytokines can amplify the inflammatory response induced by injury, instead of resolving the inflammation such as that by the pro-resolving effects induced by adipose derived mesenchymal stem cells and fibroblasts acquired from skin tissue.

Using a "systems therapeutic for physiological renormalization" approach to vaccine development. Covid-19 as an example.

Current vaccines for Covid-19 have failed to prevent the disease from spreading and have allowed more transmissible and virulent variants to form through mutations and recombinations as they replicate during the massive spread of the virions. Here I suggest using a "systems therapeutic" vaccine and dosing strategy to induce "physiological renormalization" to induce mimicry in the innate and adaptive immune systems in the respiratory tracts and sera, similar to that when the body encounters the natural infectious agent.

Neuroprotection of retinal ganglion cells in vivo using the activation of the endogenous cannabinoid signaling system in mammalian eyes.

Cannabinoid and glutamatergic signaling systems in the human retina coexist and greatly influence one another. Under glaucomatous conditions, excess levels of glutamate accrete in the retinal ganglion cell (RGC) layer. The present study tests the putative neuroprotective effect mediated by cannabinoids at the CB1 and CB2 receptors. In the first experiment, mice were given intravitreal injections of 160 nmol N-methyl-d-aspartic acid (NMDA) in one eye and saline in the paired eye. In the second experiment, both eyes were given NMDA, while one of the two was additionally given the cannabinoid agonist WIN 55,212-2. Ten days later, animals were perfused and the retinae were dissected as wholemounts and stained with Cresyl Violet. Quantitative analysis revealed that 70% of the neurons in the retinal ganglion cell (RGC) layer exposed to NMDA underwent cell death. The addition of the cannabinoid CB1/CB2 agonist doubled the number of neurons surviving the NMDA treatment. These data provide evidence that cannabinoids, either exogenous or endogenous, may be harnessed to provide protection from neurodegenerative diseases, including glaucoma, and from glutamate-induced, and potentially other forms of neurotoxicity, under chronic or acute conditions.

Stem cells part of the innate and adaptive immune systems as a therapeutic for Covid-19.

Some stem cell types not only release molecules that reduce viral replication, but also reduce the hypercytokinemia and inflammation induced by the immune system, and have been found to be part of the innate and adaptive immune systems. An important component of the stem cell's ability to ameliorate viral diseases, especially the complications post-clearance of the pathogen, is the ability of adult stem cells to reset the innate and adaptive immune systems from an inflammatory state to a repair state. Thus, the molecules released from certain stem cell types found to be safe and efficacious, may be an important new means for therapeutic development in Covid-19, especially for late-stage inflammation and tissue damage once the virus has cleared, particularly in the aged population.

Remediation of Mild, Acute Radiation Dermatitis Using a Stem Cell-Based Topical: A Real-World Case Report.

INTRODUCTION: Wounds of the skin induced by irradiation involve a disruption of skin homeostasis and an increase in inflammation. Physiological renormalization treatment strategies using the molecules released from stem cells that restore proteostasis and regulate the immune system and reduce inflammation may be effective in treating skin conditions. Previous studies of severe radiation dermatitis found a significant reduction in symptoms using a combination product of the secretome from adipose mesenchymal stem cells and dermal fibroblasts, but mild radiation dermatitis has yet to be studied using this product. CASE PRESENTATION: This is a case report of radiation dermatitis in a patient with an uncommon cutaneous basosquamous cell carcinoma with perineural invasion that warranted radiation therapy. In this study we used S2RM technology, a proprietary combination of stem cell-released molecules from multiple types of skin stem cells, to renormalize homeostasis of the skin, including a renormalization of proteostasis to treat a mild form of radiation dermatitis induced by Intensity Modulated Radiation Therapy. Dramatic reductions in pain, redness, and inflammation, more rapid and complete wound healing, and an overall enhancement of the appearance of the skin were achieved in this patient. DISCUSSION: The current study demonstrates that as part of the palliative care strategies for cancer patients, the simple topical application of S2RM technology is a powerful means to renormalize homeostasis of the skin and remediate mild radiation dermatitis. The reduction of inflammation in the skin is important to reducing systemic inflammation and related comorbidities.

The safety of a therapeutic product composed of a combination of stem cell released molecules from adipose mesenchymal stem cells and fibroblasts.

AIM: We sought to determine the safety profile of a therapeutic candidate composed of the released molecules from a combination of human adipose-derived mesenchymal stem cells and fibroblasts. Although stem cells, their progenitor cells and the molecules that are released from these cells have some demonstrated therapeutic value, much more needs to learn about the efficacy, mechanism of action and the safety profiles of these stem cell-based therapeutics. METHODS: A number of cellular, in vitro, in vivo and human studies were performed to analyze cellular, tissue and systemic safety profiles of the combinatorial product. RESULTS: At the levels tested in this study, ranging from demonstrated therapeutic doses to supratherapeutic doses, the combinatorial product demonstrated an excellent safety profile in all in vitro, cellular, tissue and systemic studies. CONCLUSIONS: We found evidence that a therapeutic candidate composed of the molecules released from human adipose-derived mesenchymal stem cells and human fibroblasts has an excellent safety profile, and that the product warrants further studies for safety and efficacy where dosing may include topical application, injection and oral application.

Better preventing and mitigating the effects of Covid-19.

Currently, there are no proven medical treatments against SARS-CoV-2, the virus responsible for Covid-19. In addition to the all important public health measures needed to prevent the spread of this disease, a number of strategies related to our exposome are recommended herein, to better prevent and mitigate the effects of a SARS-CoV-2 infection through enhancement of our immune system and reduction of inflammation.

The Safe and Efficacious Use of Secretome From Fibroblasts and Adipose-derived (but not Bone Marrow-derived) Mesenchymal Stem Cells for Skin Therapeutics.

Stem cell-based products are rapidly emerging in the marketplace as topical skin care and wound care products. Confusion is prevalent among healthcare providers and end-users about these products. Adipose-derived stem cells, fibroblasts, platelets, and bone marrow-derived stem cells are the most common cells used for stem cell therapeutic development, medical procedures, and skin care products. In this review, the significant advantages of adipose-derived stem cells and fibroblasts in terms of safety and efficacy are highlighted and compared to relatively risky platelets and bone marrow stem cells.

Rescue of degenerating neurons and cells by stem cell released molecules: using a physiological renormalization strategy.

Evidence suggests that adult stem cell types and progenitor cells act collectively in a given tissue to maintain and heal organs, such as muscle, through a release of a multitude of molecules packaged into exosomes from the different cell types. Using this principle for the development of bioinspired therapeutics that induces homeostatic renormalization, here we show that the collection of molecules released from four cell types, including mesenchymal stem cells, fibroblast, neural stem cells, and astrocytes, rescues degenerating neurons and cells. Specifically, oxidative stress induced in a human recombinant TDP-43- or FUS-tGFP U2OS cell line by exposure to sodium arsenite was shown to be significantly reduced by our collection of molecules using in vitro imaging of FUS and TDP-43 stress granules. Furthermore, we also show that the collective secretome rescues cortical neurons from glutamate toxicity as evidenced by increased neurite outgrowth, reduced LDH release, and reduced caspase 3/7 activity. These data are the first in a series supporting the development of stem cell-based exosome systems therapeutics that uses a physiological renormalization strategy to treat neurodegenerative diseases.

Gut dysbiosis, leaky gut, and intestinal epithelial proliferation in neurological disorders: towards the development of a new therapeutic using amino acids, prebiotics, probiotics, and postbiotics.

Here we offer a review of the evidence for a hypothesis that a combination of ingestible probiotics, prebiotics, postbiotics, and amino acids will help ameliorate dysbiosis and degeneration of the gut, and therefore promote restoration of nervous system function in a number of neurological indications.

The role of microbiota, and probiotics and prebiotics in skin health.

During the past decade, scientists have made great strides in understanding the microbiome's role in human health. Today, the microbiome has become key in scientific research, therapeutic development, medical treatment, and as a news feature in the media. Most studies have focused on the microbiome of our gut, but recently researchers have turned their attention to other microbiomes, including that of the skin. These studies of gut and skin microbiomes are yielding very informative results, new treatment strategies, and the development of new prebiotic and probiotic products for the treatment of many skin conditions.

Amyotrophic lateral sclerosis as a protein level, non-genomic disease: Therapy with S2RM exosome released molecules.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease that leads to death. No effective treatments are currently available. Based on data from epidemiological, etiological, laboratory, and clinical studies, I offer a new way of thinking about ALS and its treatment. This paper describes a host of extrinsic factors, including the exposome, that disrupt the extracellular matrix and protein function such that a spreading, prion-like disease leads to neurodegeneration in the motor tracts. A treatment regimen is described using the stem cell released molecules from a number of types of adult stem cells to provide tissue dependent molecules that restore homeostasis, including proteostasis, in the ALS patient. Because stem cells themselves as a therapeutic are cumbersome and expensive, and when implanted in a host cause aging of the host tissue and often fail to engraft or remain viable, only the S2RM molecules are used. Rebuilding of the extracellular matrix and repair of the dysfunctional proteins in the ALS patient ensues.

Therapeutics from Adult Stem Cells and the Hype Curve.

The Gartner curve for regenerative and stem cell therapeutics is currently climbing out of the "trough of disillusionment" and into the "slope of enlightenment". Understanding that the early years of stem cell therapy relied on the model of embryonic stem cells (ESCs), and then moved into a period of the overhype of induced pluripotent stem cells (iPSCs), instead of using the model of 40 years of success, i.e. adult stem cells used in bone marrow transplants, the field of stem cell therapy has languished for years, trying to move beyond the early and poorly understood success of bone marrow transplants. Recent studies in the lab and clinic show that adult stem cells of various types, and the molecules that they release, avoid the issues associated with ESCs and iPSCs and lead to better therapeutic outcomes and into the slope of enlightenment.

Systems biology approach to developing S(2)RM-based "systems therapeutics" and naturally induced pluripotent stem cells.

The degree to, and the mechanisms through, which stem cells are able to build, maintain, and heal the body have only recently begun to be understood. Much of the stem cell's power resides in the release of a multitude of molecules, called stem cell released molecules (SRM). A fundamentally new type of therapeutic, namely "systems therapeutic", can be realized by reverse engineering the mechanisms of the SRM processes. Recent data demonstrates that the composition of the SRM is different for each type of stem cell, as well as for different states of each cell type. Although systems biology has been successfully used to analyze multiple pathways, the approach is often used to develop a small molecule interacting at only one pathway in the system. A new model is emerging in biology where systems biology is used to develop a new technology acting at multiple pathways called "systems therapeutics". A natural set of healing pathways in the human that uses SRM is instructive and of practical use in developing systems therapeutics. Endogenous SRM processes in the human body use a combination of SRM from two or more stem cell types, designated as S(2)RM, doing so under various state dependent conditions for each cell type. Here we describe our approach in using state-dependent SRM from two or more stem cell types, S(2)RM technology, to develop a new class of therapeutics called "systems therapeutics." Given the ubiquitous and powerful nature of innate S(2)RM-based healing in the human body, this "systems therapeutic" approach using S(2)RM technology will be important for the development of anti-cancer therapeutics, antimicrobials, wound care products and procedures, and a number of other therapeutics for many indications.

Maturing from embryonic to adult policy on stem cell therapeutics.

The National Institutes of Health (NIH) closure of the agency's Center for Regenerative Medicine (CRM), which focused on therapeutic development of induced pluripotent stem cells (iPS), was caused by the lack of progress in practical development of the iPSs for use in human therapies. As the NIH evaluates priorities in future stem cell therapeutic development, adult stem cell processes in the human body need to be prioritized for a number of key reasons, including (1) adult stem cells release many types of molecules that provide much of the therapeutic benefit of stem cells and (2) adult stem cells and somatic cells exist in a state of dynamic transition between different potency levels and can be naturally driven by the microenvironment to a state of pluripotency. Thus, the study and development of adult stems for therapeutic use can include naturally induced pluripotent stem cells (NiPSs) that lack the problematic genetic and epigenetic reprogramming errors found in iPSs.

Systems biology approach to developing "systems therapeutics".

The standard drug development model uses reductionist approaches to discover small molecules targeting one pathway. Although systems biology analyzes multiple pathways, the approach is often used to develop a small molecule interacting at only one pathway in the system. Similar to that in physics where a departure from the old reductionist "Copenhagen View" of quantum physics to a new and predictive systems based, collective model has emerged yielding new breakthroughs such as the LASER, a new model is emerging in biology where systems biology is used to develop a new technology acting at multiple pathways called "systems therapeutics."

Enhancing spontaneous stem cell healing (Review).

Adult stem cells are distributed throughout the human body and are responsible to a great extent for the body's ability to maintain and heal itself. Accumulating data since the 1990s regarding stem cells have demonstrated that the beneficial effects of stem cells are not restricted to their ability to differentiate and are more likely due to their ability to release a multitude of molecules. Recent studies indicated that ≤80% of the therapeutic benefit of adult stem cells is manifested by the stem cell released molecules (SRM) rather than the differentiation of the stem cells into mature tissue. Stem cells may release potent combinations of factors that modulate the molecular composition of the cellular milieu to evoke a multitude of responses from neighboring cells. A multitude of pathways are involved in cellular and tissue function and, when the body is in a state of disease or trauma, a multitude of pathways are involved in the underlying mechanisms of that disease or trauma. Therefore, stem cells represent a natural systems-based biological factory for the production and release of a multitude of molecules that interact with the system of biomolecular circuits underlying disease or tissue damage. Currently, efforts are aimed at defining, stimulating, enhancing and harnessing SRM mechanisms, in order to develop systems-based methods for tissue regeneration, develop drugs/biologics or other therapeutics and enhance the release of SRM into the body for natural healing through proper dietary, exercise and other lifestyle strategies.