Immunogenicity

Low-immunogenicity phenotype permits the use of allogeneic cells for patients and strongly reduces the risk of allograft rejection. No immunosuppressive therapy is needed.

Immune modulating functions

Provide damaged tissue with a relatively stable environment, which is beneficial for tissue repair. Capable of polarized differentiation.

Tissue remodeling

Fibrosis - excessive deposition of extracellular matrix (ECM) components, including collagen, proteoglycan, fibronectin, etc.

Physiological fibrosis is protective in response to the injury.

Pathological outcomes of progressive fibrosis due to a range of causes/triggers usually lead to fibrogenic scarring of tissues.

Fibrotic effect:

• give rise to the osteoblasts, chondrocytes and adipocytes, fibroblasts.

Anti-fibrotic:

• decreased endothelial permeability and protection of cell growth (KGF and HGF factors);
• MFGE8 factor;
• Interleukin-1 receptor antagonist;
• regulation of angiotensin II type 1 receptor (AT1R) and platelet-derived growth factor-β (PDGF-β).

Role of UC-MSCs in angiogenesis

Angiogenesis, the formation of new blood vessels, is a vital process in tissue wound healing that is a targeted by many pharmacologic agents to treat disorders such as myocardial ischemia, ischemic stroke, and diabetic retinopathy.

Preclinical studies in cardiac and brain ischemia support the concept that UC-MSCs improve structural and functional outcomes by repairing and stimulating the growth of blood vessels. The angiogenic properties of MSCs are mediated through the release of:

• hypoxia inducible factor
• vascular endothelial growth factor
• angiopoietin
• erythropoietin.

The ability to repair vascular injury after administration of MSCs has been supported in studies of:

• diabetic peripheral vascular disease
• cutaneous wound repair
• and bone necrosis.

Global trends

After several decades of preclinical research, over 1000 clinical trials, and tens of thousands of patients, MSCs have exhibited an excellent safety record. Of these cells, the growth in interest for clinical uses of MSCs with umbilical cord origin (UC-MSCs) has been the most prolific of all.

Examples of Therapy

UC-MSCs as critical COVID-19 adjuvant therapy

One of the main causes of acute respiratory distress syndrome in coronavirus disease 2019 (COVID-19) is cytokine storm, although the exact cause is still unknown. Umbilical cord mesenchymal stromal cells (UC-MSCs) influence proinflammatory T-helper 2 (Th2) cells to shift to an anti-inflammatory agent.

To investigate efficacy of UC-MSC administration as adjuvant therapy in critically ill patients with COVID-19, conducted a double-blind, multicentered, randomized controlled trial at four COVID-19 referral hospitals in Jakarta, Indonesia has been done.

Results:

• Survival rate in the UC-MSCs group was 2.5 times higher.
• In patients with comorbidities, UC-MSC administration increased the survival rate by 4.5 times compared with controls.

Another clinical trial (NCT04288102) also illustrated positive effects of UC-MSCs on lung damage in severe COVID-19 patients.

101 severe COVID-19 patients with lung damage were recruited and randomly divided at a 2:1 ratio. 66 patients received three doses of 4 × 107 cells UC-MSCs intravenously on Day 0, 3, and 6, while 35 patients received placebo infusions.

Results:

Patients in the UC-MSCs group demonstrated significantly reduced the proportions of solid component lesion volume with median difference of -15.45%.

The six-minute walking distance was also 27 m longer in the treatment group.

UC-MSCs in the treatment of multiple sclerosis (Clinical case)

The patients with MS were recruited and treated with UC-MSC. After treatment, the clinical therapeutic effects including symptoms, vital signs, clinical attacks, magnetic resonance imaging (MRI), neurological function scores and adverse reactions such as fever, dizziness, and vascular irritation were monitored and evaluated. In addition, the regulatory effects of UC-MSC on immune system of patients were also assessed.

Results:

After cell treatment, the symptoms involved in unstable walking lessened, mental state, appetite, coordination ability and balance force of patient 1 were remarkably improved.

The symptoms including numbness of the right limbs, constipation of patient 2 were mitigated.

At the same time, mental status and memory of patient 2 were also improved, indicating the patient’s condition was stable.

However, the symptoms and vital signs of patient in control group did not improve.

UC-MSCs transplantations for cerebral palsy (Clinical case)

A case of a 4-year-old boy with abnormalities of muscle tone, movement and motor skills, as well as unstable gait leading to frequent falls. The results of the electroencephalogram (EEG) indicate moderately abnormal EEG, accompanied by irregular seizures. Based on these clinical characteristics, the patient was diagnosed with cerebral palsy (CP).

The patient was treated with umbilical cord mesenchymal stem cell (UC-MSC) transplantation therapy.

Results:

After three successive cell transplantations, the patient recovered well and showed obvious improvements in EEG and limb strength, motor function, and language expression.

A case study on autism spectrum disorder treatment using UC-MSCs

Patients who were aged between 3 and 7 years with a confirmed diagnosis of ASD were enrolled. All children at Hospital who had severe ASD (Childhood Autism Rating Scale [CARS] scores >60) were recruited for this study.

Results:

The treatment of ASD using uncultured UC-MSCs has improved the symptoms of ASD. Particularly, ASD patients increased social participation, building relationships, and verbal communication ability to form relationships with other people.

Summary

UC-MSCs are strongly expanding candidates for a high unmet medical need in treat wide range of conditions, regenerative medicine, largely due to their regenerative characteristics such as self-renewal, secretion of trophic factors, and the capability of inducing mesenchymal cell lineages.

UC-MSCs also possess homing and trophic properties modulating immune system, influencing microenvironment around damaged tissues and enhancing tissue repair, thus offering a broad perspective in cell-based therapies.

Exosomes are cheaper alternative to mesenchymal stem cells.

They are similar to MSCs in their low immunogenicity and ability to reduce inflammation, modulate the activity of immune cells, and migrate to the injured site, such as a stroke lesion.

Naturally, their content depends significantly on the condition of the source MSCs because these cells are highly responsible to the cues from the microenvironment, both in vitro and in vivo.

In addition to that, they have a number of advantages.

Firstly, a cell-free product is good for several reasons. Comparing to live mesenchymal stem cells, exosomes are suitable for long term storage without loss of their regenerative, anti-inflammatory and stimulatory properties.

And they are more stable compared to MSCs because, unlike cells, exosomes cannot change their cytokine and enzymatic profile after secretion.

Secondly, exosomes contain high concentrations of miRNA – small regulatory RNAs that regulate the translation and transcription of specific mRNAs. Micro-RNAs are small single-strand RNAs that bind the 3’ or 5’ untranslated regions of specific matrix RNAs, or with promoters of certain genes. The result is selective mRNA degradation, inhibited translation, or regulation of transcription. Micro-RNA-dependent pathways are often involved in the pathogenesis of many diseases, so exosomes add yet another opportunity to reverse the pathological process.

Also, exosomes can pass the blood-brain barrier due to their small size. It is especially valuable in stroke and chronic brain diseases.

What is known about the treatment of specific diseases using MSC exosomes?

Most of the pathological disease processes develop chronic inflammation of the associated tissues that results in activation of immune responses and eventually leads to degeneration via several compensatory mechanisms.

Reduction of the local inflammation is a key to the tissue regeneration and mesenchymal stem cells derived exosomes are ideal candidates for such therapy.

How exactly do exosomes work in the nervous system?

Studies have shown that all the signal molecules and microRNAs have a regenerative and anti-inflammatory effect. Most importantly, they stimulate the differentiation of neural progenitor cells into mature neurons in substantia nigra via brain-derived neurotrophic growth factor signaling.

They send survival signals to existing neurons, preventing their apoptosis.

Exosomes also reduce neuroinflammation, which is heightened in Parkinson’s, by switching the microglia to an anti-inflammatory phenotype and decreasing the synthesis of reactive oxygen species in immune cells and astrocytes. Besides, their endothelial growth factors stimulate the growth of blood vessels, which degenerate when neurons die.

Osteoarthritis

Mesenchymal stromal cells are known to decrease inflammation, promote cartilage regeneration, reduce pain, and improve the functionality of the joints in osteoarthritis.

Such effects are achieved by mesenchymal paracrine factors. The same cocktail of factors is contained in exosomes, providing a cheaper and more concentrated alternative to live MSC.

Cardiovascular diseases

Stroke, myocardial infarction, peripheral arterial disease, and atherosclerosis - remain a significant cause of mortality and disability. In most cases, an acute episode such as a stroke is preceded by gradual deterioration of the vasculature, mostly due to cholesterol accumulation in the arteries and the resulting inflammation and clogging.

MSCs and exosomes could both slow down the chronic stage and accelerate recovery after an acute episode.

Crohn’s disease

Crohn’s disease is an autoimmune condition characterized by persistent inflammation of the intestines. Every third patient develops fistulas, which are often resistant to both surgical and pharmacological interventions. MSCs or their exosomes could alleviate this inflammation to achieve long-term fistula healing and improvement in the quality of life.

Acute respiratory distress syndrome (ARDS)

During the COVID-19 pandemic, MSC attracted interest as a pleiotropic agent against the cytokine storm, a life-threatening systemic inflammation caused by severe viral infection. RNA multiplication inside host cells, T-cell and macrophage activation in response to the virus, and evasion of immune response create a vicious circle of intensifying inflammation.

BM-MSC were found to be safe for COVID patients with acute respiratory distress syndrome, but exosomes could be even safer because of their zero risk of teratogenesis and clumping/embolism. MSC exosomes have what is needed to stop the cytokine storm in severe COVID-19 or other acute lung disease.

To conclude, exosomes are one of the key mechanisms of action of mesenchymal stromal cells, which makes them a safe but still effective alternative to cell therapy.

They are helpful whenever excessive inflammation leads to disease: neural degeneration, cardiovascular diseases, inflammatory bowel disease, osteoarthritis, or acute pneumonia.

List of benefits

• Anti-inflammatory effects: MSC exosomes have been shown to have anti-inflammatory effects, which may make them useful in treating inflammatory disorders such as arthritis and inflammatory bowel disease.
• Immunomodulatory effects: MSC exosomes have the ability to modulate the immune system, making them potential candidates for treating autoimmune diseases.
• Tissue repair and regeneration: MSC exosomes have been shown to promote tissue repair and regeneration, which may make them useful in treating injuries and degenerative diseases.
• Neuroprotective effects: MSC exosomes have been shown to have neuroprotective effects, which may make them useful in treating neurological disorders such as Parkinson's disease and Alzheimer's disease.
• Drug delivery: MSC exosomes have the potential to be used as drug delivery vehicles, as they can cross biological barriers and deliver therapeutic molecules to target cells.

Anti-ageing and cosmetological implementation of Exosomes

Exosome therapy is a new frontier in regenerative skincare and anti-aging medicine.

Used for a long time for the treatment of skin diseases such:

• Wounds and Ulcers
• Burn Injuries
• Recessive Dystrophic Epidermolysis Bullosa
• Psoriasis
• Atopic Dermatitis
• Scleroderma
• Hypertrophic Scars
• Other Dermatological Pathologies

Exosomes have become the ultimate alternative and new favorite Skin-Rejuvenation Treatment.

Skin changes are among the most visible signs of aging.

• Loss of Face Volume
• Sagging Skin
• Wrinkles
• Dull Skin
• Age Spots
• Skin Tags
• Dry, Itchy Skin

Most Common Anti-Aging Treatments:

• Botulinum Toxin Therapy
• Dermabrasion
• Chemical Peels
• Laser Skin Resurfacing
• Fillers
• Plastic surgery

In contrast to other methods, exosomes affect the pathway thus preventing manifestations of changes.

MSC-derived exosomes contribute to the result by several mechanisms:

• Anti-inflammatory
• Regenerative
• Stimulation of cell renewal
• Stimulates collagen synthesis
• Reduces melanin synthesis
• Reduces the amount of free radicals
• Moisturizes
• Deeply restores the skin
• Stimulates intensive skin regeneration
• Helps reduce scarring

Advantages of MSC-derived exosomes for regenerative therapy:

• Exert intense biological effects because of their direct fusion with target cells
• Can be stored and transported for long periods of time since their effective components
• Are protected by their membrane, which is not easily destroyed
• The concentration, dose, route and time of use are easy to control
• There is no risk of the immune rejection and tumorigenesis caused by cell
• Transplantation therapy
• Exosomes can be sterilized by filtration during their preparation for clinical usage

Recommendations for use:

• Women and men of different ages
• All skin types
• All areas of the skin that need regeneration activation and stimulation (face, neck, décolleté, arms, hands and other)

Exosomes have potential applications in modern cosmetology and can be combined with the following methods:

MICRONEEDLING: Microneedling is a technique that involves using tiny needles to create small punctures in the skin. This stimulates collagen production and enhances the absorption of topical treatments, including exosomes applications.

LASER THERAPY: Laser therapy can be used to improve skin tone, reduce the appearance of wrinkles and fine lines. Laser therapy also promotes collagen production. When combined with exosomes, laser therapy can help to maximize the rejuvenating effects of the treatment.

PLATELET-RICH PLASMA (PRP) THERAPY: PRP therapy involves injecting a concentrated solution of the patient's own platelets into the skin to promote tissue repair and regeneration. When combined with exosomes, PRP therapy can help to enhance the healing and Revitalizing impact of the skincare procedure.

MESOTHERAPY: Mesotherapy involves injecting a cocktail of vitamins, minerals, and other nutrients into the skin to improve its health and appearance. When combined with exosomes, mesotherapy can help to maximize reinvigorating outcomes of the skincare method.

CHEMICAL PEELS: Chemical peels involve applying a solution to the skin that causes the outer layer to peel off, revealing smoother, brighter skin underneath. When combined with exosomes, chemical peels can help to promote collagen production and enhance the overall restorative benefits of the skin rejuvenation process.