Stem cell therapy

Stem cells are different. Used for various tasks. In addition to medical therapeutic technologies, there are safe wellness programs.

Every year the sphere of application of stem cells for the treatment of various diseases and maintaining health is expanding.

Chromosomal changes in hematopoietic cells are an inevitable event in aging. Accordingly, it is possible to periodically carry out actually “replacement therapy”, similar to the situation with type 1 diabetes mellitus, when the pancreas, for a number of reasons, is not able to produce its own insulin. By replacing the aged cells with their own younger ones in this way, the aging process can be significantly slowed down. www.nature.com/articles/s41586-020-2426-2

Transplanted human hematopoietic stem cells have their own DNA age, which is not affected by the environment in a recipient of a different age.

doi.org/10.1101/2022.01.18.476756

With age, the number of stem cells decreases significantly, moreover: their potential decreases — that is why it is fundamentally important to prepare your own stem cells at a young age for possible further use.

Stem cells are used in a new medical technology for the restoration of polyclonal hematopoiesis using HSC.

The largest amount of stem cells available for removal is found at the time of birth in the umbilical cord blood. 100 milliliters of cord blood contains as many stem cells as a liter of bone marrow.

With age, the number of stem cells in the body decreases catastrophically. In a newborn, 1 stem cell occurs in 10 thousand, by the age of 20-25 — 1 in 100 thousand, by 30 — 1 in 300 thousand. By the age of 50, only 1 stem cell per 500,000 remains in the body. The depletion of stem cells due to aging or serious illness deprives the body of the ability to self-repair. Because of this, the vital activity of certain organs becomes less efficient.

Atherosclerosis is directly related to age. Bone marrow age dictates the clonality of smooth muscle cells in atherosclerotic plaque. Aging is the predominant risk factor for atherosclerosis, the leading cause of death. Rare smooth muscle cell (SMC) progenitor cells proliferate clonally to give rise to approximately 70% of atherosclerotic plaque cells. Bone marrow-derived (BM) cells have been found to autonomously induce SMC polyclonality and worsen atherosclerosis. Replacing the HSC stops the process. doi.org/10.1101/2022.01.18.476756

SAFETY

A meta-analysis over 15 years showed complete safety with few rare side effects. 62 randomized clinical trials involving 3546 participants diagnosed with various diseases (about 20 types of diseases) who received intravenous or local implantation compared with placebo or no treatment.

The pooled analysis showed that MSC administration was strongly associated with transient fever, injection site side effects (redness), constipation, fatigue, and insomnia. MSC administration tended to decrease rather than increase the incidence of arrhythmia. pubmed.ncbi.nlm.nih.gov/34663461/

Another meta-analysis showed that MSC therapy is effective and safe in diabetic patients. pubmed.ncbi.nlm.nih.gov/33705413/

We officially enter into a contractual relationship with the patient having all the permits within the framework of scientific programs since 2012. During this period, no side effects or complications were noted. About 40-50,000 hematopoietic stem cell transplantations are performed annually in the world. In the US alone, over the past 30 years, 1 million patients have been treated with their own stem cells from various sources. And in 2012, the European Association for Bone Marrow Transplantation announced the one millionth patient who had received a peripheral blood stem cell transplant.

We use cell therapy with different types of stem cells at our clinical bases in different countries: the Kingdom of Thailand, Russia for the consequences of type 1 and type 2 diabetes in children and adults (neuropathy), spinal cord and brain injuries, as well as in special programs for healthy people with with the aim of improving the quality of life, active longevity and achieving a proven age reversal.

Mesenchymal stem cell (MSC) transplantation is a promising solution for stopping immune aging, as the cells have excellent immunomodulatory functions and low immunogenicity.

www.mdpi.com/1422-0067/22/11/5749/htm

 

Currently, we use this type of stem cells to a limited extent for the treatment of diabetes mellitus in children and adolescents.

Type 1 diabetic patients treated with cord blood SC rarely return hyperglycemia in NOD mice, but they show profound immunomodulatory properties in humans. www.ncbi.nlm.nih.gov/pmc/articles/PMC3591677

Umbilical plasma injections reduce a person’s biological age.

www.pubmed.ncbi.nlm.nih.gov/36052758/

СТВОЛОВЫЕ КЛЕТКИ МОБИЛИЗОВАННЫЕ ИЗ ЖИРОВОЙ ТКАНИ

Adipose tissue is a more easily accessible biological material compared to bone marrow, the main source of MSCs. MSCs derived from adipose tissue are better suited for use in traumatology and orthopedics, as they differentiate more efficiently into bone tissue cells. In addition, adipose tissue MSCs can stimulate vascular growth through the secretion of vascular endothelial growth factor (VEGF), which makes them effective in diseases such as lower limb ischemia.

                               TYPE 1 DIABETES THERAPY

MSCs isolated from patients with type 1 diabetes recently after diagnosis do not show phenotypic or functional impairment as a result of deleterious inflammatory and metabolic diabetic conditions. This allows the use of MSCs for the treatment of patients with newly diagnosed DM1.

pubmed.ncbi.nlm.nih.gov/26781648/

Stem cell therapy requires a large number of human cells of a particular type. Exposure of near-infrared laser to adult stem cells derived from human body fat causes stem cells to proliferate 54% faster. After that, with the help of a green laser, stem cells are transformed into different types of cells faster and more reliably.

Red (600–700 nm) and near infrared (780–1100 nm) wavelengths promote cell proliferation. Wavelengths of light such as green (495–570 nm) have been found to affect ADMSC differentiation (undifferentiated adipose-derived mesenchymal stem cells).

www.sciencedirect.com/science/article/pii/S0300908421001838

We use therapy with autologous activated MSCs mobilized from adipose tissue in vitro followed by transplantation.

Adult stem cells are found in many tissues and organs, including adipose tissue. They are usually found in a special microenvironment called a «stem cell niche». They remain dormant under normal conditions and are activated when there is a need to repair or preserve damaged tissue. However, when isolated and cultured in vitro or ex vivo, stem cells have a limited ability to proliferate and differentiate. But, low intensity laser therapy (LLLT) stimulates the proliferation of many types of cultured cells, including stem cells.

www.spiedigitallibrary.org/eBooks/TT/Low-Level-Light-Therapy-Photobiomodulation/Chapter8/Low-Level-Laser-Therapy-and-Stem-Cells/10.1117/3.2295638.ch8

 

Relationships between HSCs and their supporting niche cells are functionally impaired in old age. But, the senile hematopoietic system can be restored by young mobilized peripheral blood, HSC. MicroRNAs in secreted microvesicles are responsible for improving hematopoietic functions by increasing the expression of genes targeting MYC and E2F and decreasing p53 expression. During recovery, an increase in the number of NK killers was observed, which could eliminate senescent cells as they appeared in various organs. The regenerated cells may also assist in the regeneration of aged hematopoietic and non-hematopoietic supporting cells in the bone marrow microenvironment.

www.journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0050201

www.aging-us.com/article/203689/text

We develop, conduct clinical trials and introduce into the clinic new methods of influencing the extracellular matrix.

CHELILATION

Accumulation of macromolecular damage (especially in extracellular matrix (ECM) protein, nuclear pore complex (NPC) protein and histones) is a concomitant feature of aging. Stochastic non-enzymatic modifications of the ECM trigger cellular senescence, as well as many other signs of aging that are characteristic of the composition of organic barriers and lead to tissue fibrosis. This makes the extracellular matrix a key target for interventions.

One of the most effective methods for assessing organ and tissue retention of heavy metals is to compare urinary heavy metal levels before and after administration of a pharmaceutical chelating agent such as EDTA, DMSA, or DMPS. Therefore, we always conduct a study (analysis) of urine and blood in dynamics after chelation therapy.

www.sciencedirect.com/science/article/pii/S1568163720302324

CHELATION AND EXTRACELLULAR MATRIX

The accumulation of damage in macromolecules (especially extracellular matrix (ECM) proteins, nuclear pore complex (NPC) proteins and histones) is a concomitant feature of aging. Stochastic non-enzymatic modifications of the ECM trigger cellular senescence, and many other signs of aging affect the integrity of organ barriers and lead to tissue fibrosis. This makes the extracellular matrix a key target for interventions. The most promising correction strategies may be AGE inhibitors (chelators, compounds of the O-acetyl group or compounds with transglycation activity, amadorins and amadoriases), glucose degrading agents, elastogenesis stimulants and RAGE antagonists.

www.sciencedirect.com/science/article/pii/S1568163720302324

 

CAR T-cell therapy is a form of immunotherapy that uses specially modified T-cells — part of the immune system — to fight various diseases: cardiovascular, cancer and even age! A sample of a patient’s T cells is taken from the blood, then modified to produce special structures called chimeric antigen receptors (CARs) on their surface.

 

We develop, conduct clinical trials and introduce into the clinic new methods of cancer therapy using cellular (CAR-T) therapy with trogocytosis.

Tumor factors stimulate trogocytosis, a process derived from the Greek word trogo, which means to gnaw or chew. When T cells interact with cancer cells, they can sometimes bite off part of the cancer cell’s membrane. When this membrane segment includes an antigen, a cancer-specific molecule, T cells can then begin to express that antigen on their own cell surface, making it look like a cancer cell to other T cells.

ATF3 gene, opposes CH25H activity. Elimination of AFT3 prevents the occurrence of trogocytosis and restores the ability of T cells to kill tumor cells. Since trogocytosis may reduce the efficiency of engineered T cells delivered to CAR T, blocking it may improve the efficiency of CAR T. Delivery of CAR T cells enriched in CH25H improves the survival of animal models with cancer compared to unarmored CAR T cells. www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00350-3

Recently, CAR-T therapy has been considered as a targeted therapy for aging.

www.nature.com/articles/s41586-020-2403-9

We are developing new therapy strategies. age-related diseases, including the cardiovascular system. doi.org/10.1016/j.arr.2020.101072

Your behavior and environment can lead to changes that affect how your genes work. Unlike genetic changes, epigenetic changes are reversible and do not change the DNA sequence, but they can change how your body reads the DNA sequence. In biology, epigenetics is the study of inherited changes in the phenotype that are not related to changes in the DNA sequence.

Tissue stem cells sense their environment, and this perception affects their future fate and function. Stem cells accumulate epigenetic memories of various environmental events. Stem cells carry the memory of their original niche, migration, encounters with inflammation, and adaptation to new fates and challenges. www.science.org/doi/10.1126/science.abh2444

Analysis of clones of individual stem cells showed that methylation changes during senescence are stochastic. The lifespan of MSC (mesenchymal stem cell) populations can vary greatly due to the accumulation of (random) epigenetic aberrations. onlinelibrary.wiley.com/doi/full/10.1111/acel.12544

Stem cell dysfunction is a sign of aging. Epigenetic changes play a critical role in the loss of stem cell function with age.

Recovery of nuclear acetyl-CoA via ectopic expression of CiC or addition of acetate to MSCs in culture rejuvenates MSCs, restoring the potential for efficient differentiation into an osteogenic lineage. Citrate, which has recently been reported to prolong lifespan in Drosophila, chemically includes acetyl-CoA and may be useful in restoring cytoplasmic and nuclear levels of acetyl-CoA. The general applicability of the CiC defect to old cells, especially stem cells, should be established.
Chromatin remodeling due to citrate degradation impairs osteogenesis of aged mesenchymal stem cells.

doi.org/10.1038/s43587-021-00105-8

Aging is accompanied by a general decline in the function of many cellular pathways. Older mesenchymal stem cells show reduced chromatin availability and lower histone acetylation, especially at osteogenic gene promoters and enhancers. The decrease in histone acetyl-I is due to impaired mitochondrial acetyl-CoA export due to lower citrate carrier (CiC) levels. In old cells, increased lysosomal degradation of CiC is observed, which is mediated by mitochondrial vesicles. Restoration of cytosolic levels of acetyl-CoA, either through exogenous expression of CiC or by addition of acetate, reconstructs the chromatin landscape and eliminates osteogenesis defects in old MSCs. The results show an age-dependent relationship between mitochondrial quality control, chromatin, and SC fate, which are linked through CiC. www.nature.com/articles/s43587-021-00105-8

The 13-year study shows that the degradation of DNA organization and regulation, known as epigenetics, can cause aging in an organism independent of changes in the genetic code itself. The disruption of epigenetic information leads to aging in mice and that restoring the integrity of the epigenome reverses these signs of aging. This study is the first to show epigenetic changes as a major driver of aging in mammals.

www.cell.com/cell/fulltext/S0092-8674(22)01570-7

We are developing fundamentally new ways of epigenetic reprogramming by physical methods.

We use original personalized cell preparations, young plasma, blood components, exosomes for the treatment of diseases and in anti-aging medicine.

Young blood plasma has a beneficial effect on various organs of mice. More than halving the epigenetic age of blood, heart, and liver tissue. A less pronounced, but statistically significant effect of rejuvenation can be observed in the hypothalamus. www.biorxiv.org/content/10.1101/2020.05.07.082917v1.full.pdf

Altering therapeutic plasma exchange (TPE) to dilute systemic factors that become harmful when elevated with age can be a rapidly effective rejuvenation therapy that rewires important signaling pathways into adolescence. www.trasci.com/article/S1473-0502(21)00128-2/fulltext

The loss of gene expression with age is mimicked by parabiosis: aging blood reduces global gene expression, and young blood restores it in select cell types.

www.nature.com/articles/s41586-022-04461-2

Plasma from young rats transfused into old rats produces anti-aging effects.

www.liebertpub.com/doi/10.1089/rej.2020.2354

Administration of cerebrospinal fluid from young mice to old mice restores memory recall in older animals by inducing the formation of a fatty myelin sheath that insulates neurons in the brain.

www.nature.com/articles/d41586-022-00860-7

Donor blood transfusion can be an effective treatment for the consequences of a stroke.

www.nature.com/articles/s41467-020-17930-x

EXOSOMES

Exosomes are taken up by distant cells, where they can influence cell function and behavior. Intercellular communication through exosomes is involved in the pathogenesis of various diseases, including cancer, neurodegeneration, and inflammatory diseases.

EVs derived from stem cells perform the same functions as their parent cells. which may represent new therapeutic agents for the treatment of autoimmune diseases, including type 1 diabetes mellitus T1D.

www.pubmed.ncbi.nlm.nih.gov/35095751/

An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory. www.nature.com/articles/s41556-022-00991-z

Human MSC exosomes reduce cellular senescence in renal epithelial cells. doi.org/10.3390/ijms222413562

Intranasal administration of exosomes has been recognized as an effective and reliable way to bypass the blood-brain barrier (BBB) ​​and deliver drugs to the CNS. www.wiley.com/doi/full/10.1002/stem.3456

Cells in close proximity synchronize their differentiation stages and cellular phenotypes with each other through cellular communication mediated by extracellular vesicles (EV) vesicles—phenotypic cell synchrony (PSyC). PSyC is a new form of cell-to-cell communication mediated by the regulation of neighboring cells and may be widely involved in tissue development and homeostasis.

www.onlinelibrary.wiley.com/doi/10.1002/jev2.12147

Inhalation of secretome and exosomes of lung spheroid cells promotes lung recovery in pulmonary fibrosis. www.nature.com/articles/s41467-020-14344-7

MSC-derivatives of EV are highly effective senotherapeutic agents that slow down the progression of aging and diseases caused by cell senescence. doi.org/10.1111/acel.13337

Dermal exosomes with miRNA promote hair regeneration.

www.advances.sciencemag.org/content/6/30/eaba1685

Rejuvenation of mesenchymal stem cells with extracellular vesicles suppresses the increase in the level of reactive oxygen species. www.nature.com/articles/s41598-020-74444-8

                           FORMED BLOOD ELEMENTS

RBCs promote inflammation, serve as critical immune sensors through surface expression of the nucleic acid sensitive Toll-like receptor 9 (TLR9). www.science.org/doi/10.1126/scitranslmed.abj1008

 

Fibroblasts are the main cells of the connective tissue of the skin. They were discovered more than 150 years ago and named from the Latin fibra — fiber and the Greek blastos — germ, sprout.

The function of fibroblasts is the synthesis of extracellular matrix components (collagen, elastin, reticulin, hyaluronic acid), that is, what makes the skin supple and smooth. Unfortunately, the number of divisions of fibroblasts is limited from 50 to 60 divisions, after which the cells are not renewed and the skin (tissue) loses its former splendor. But, a new technology for isolating one’s own fibroblasts, reproduction and introduction into problem areas solves this problem.

Over the past 20 years, we have been using the mobilization and storage of autologous fibroblasts for cosmetic programs, not only as a renewal of the pool of our own young fibroblasts, but for remodeling the tissue niche of stem cells.
Fibroblasts found in connective tissues constitute the stem cell niche, especially in organs such as the skin. A new study has shown a redox activation mechanism of the transcription factor JunB, which, through the simultaneous activation of p16INK4A and repression of insulin growth factor-1 (IGF-1), initiates the acceleration of fibroblast aging. Fibroblast aging severely disrupts the metabolic and structural niche, and its important interactions with various stem cells thus cause depletion of stem cell pools and depletion of skin tissues.
Suppressing JunB in a fibroblast niche-specific manner – by restoring IGF-1 and p16 levels – restores skin stem cell pools and overall skin tissue integrity. www.cell.com/cell-reports/fulltext/S2211-1247(21)01077-9

Maintains a healthy and youthful condition of your skin for a long time. Mor et al. proved that when transplanting normal fibroblasts into the skin of cancer patients, no tumors form at the injection site, while transplanting cancer cells always gives tumors. Hayflick and Moorhead (1961) confirmed that normal fibroblasts do not form tumors when transplanted into cancer patients. The safety of the use of fibroblasts was studied by Keller et al., 2000, they proved that fibroblasts obtained after 60 years did not lose their ability to multiply and produce collagen. The procedure is approved for use by the FDA USA and on the territory of the Russian Federation. Our experience in the application of technology is more than twenty years.

CELL THERAPY IN COSMETOLOGY

MSCs have been recognized as therapeutic agents for skin regeneration and rejuvenation. The skin can be damaged as a result of wounds caused by cutting or tearing of tissue, as well as burns. Skin aging is a natural process that can be exacerbated by environmental pollution, exposure to ultraviolet radiation, alcohol, tobacco and malnutrition. MSCs have healing abilities that can be applied to damaged and aging skin. In skin regeneration, MSCs increase cell proliferation and neovascularization, and reduce inflammation in skin lesions. In skin rejuvenation, MSCs lead to the production of collagen and elastic fibers, inhibition of the activation of metalloproteinases, and contribute to protection against aging caused by ultraviolet radiation. MSCs derived from induced pluripotent stem cells (iPSCs) are potentially advanced MSCs that are suitable for cell therapy. www.mdpi.com/1422-0067/22/5/2410

REGENERATION OF CARTILAD TISSUE

New approaches support the concept of MSCs as signaling and modulating cells exerting their influence through trophic and immune mediation rather than as cell replacement therapy.

The advantages of allogeneic cells as a ready-to-use product with well-defined characteristics of cell surface marker expression, proliferative capacity and differentiation capacity are well known. There is more emphasis on allogeneic cell sources. Moreover, the understanding of immunomodulatory mechanisms and the role of trophic factors in the interactions of articular chondrocytes and MSCs is considered, which offer possible targets for assessing the activity of MSCs in vivo in the intra-articular environment. stemcellsjournals.onlinelibrary.wiley.com/doi/full/10.1002/sctm.20-0552

Growth factors secreted by platelets initiate genes involved in the formation of the extracellular matrix in human fibroblasts.
Whole transcriptome sequencing and gene ontology enrichment (GO) analysis of PRGF-treated fibroblasts revealed the induction of several genes involved in extracellular matrix (ECM) formation. Real-time PCR analysis of PRGF-treated fibroblasts and skin explants confirmed the induction of genes associated with ECM, specifically transforming growth factor-induced beta protein (TGFBI), fibronectin 1 (FN1), matrix metalloproteinase-9 (MMP-9), transglutaminase 2 (TGM2), fermitin family member 1 (FERMT1), collagen type I alpha 1 (COL1A1), disintegrin and metalloproteinase 19 (ADAM19), serpin family member 1 (SERPINE1) and lysyl oxidase-like 3 (LOXL3).
The induction of these genes was time dependent and partly dependent on the epidermal growth factor receptor (EGFR). Moreover, PRGF induced fibroblast migration and proliferation. Taken together, the observed effects of PRGF on human fibroblasts may contribute to the underlying mechanisms that support the beneficial wound healing effects of platelet concentrate products.

www.mdpi.com/1422-0067/22/19/10536/htm

We develop and introduce new methods of cell therapy of oncological diseases into the clinic.

Natural killer cells (NK cells) in cancer therapy

Natural killer cells (NK cells) are large granular lymphocytes with cytotoxicity against tumor cells and cells infected with viruses. Currently, NK cells are considered as a separate class of lymphocytes. Nk perform cytotoxic and cytokine-producing functions. Nk is one of the most important components of cellular innate immunity. These cells were called natural killer cells because, according to early ideas, they did not require activation to kill cells that did not carry major histocompatibility complex markers. A decrease in the amount of MHC1 on the cell surface may be due to the transformation of the cell into a cancer cell or the action of viruses such as papillomavirus and HIV. Cell therapy in oncology is carried out with targeted anti-cancer killer cells (activated natural killer cells and T cells). Cancer immunotherapy is carried out using monoclonal, polyclonal or bispecific antibodies.
Natural killer (NK) cells produce Th1 cytokines with antitumor activity when stimulated by dendritic cells bearing alpha-galactosylceramide, an analogue of the NK-activating glycolipid antigen. However, in most patients with tumors, there is not enough NA for an effective immune response, which makes it necessary to search for a source of NA that could replenish the insufficient population of endogenous cells. Induced stem cells have become such a source. We are currently using this technology to treat some cancers.