Mesenchymal Stem Cells Can Give You Younger Knees!

Most people will encounter joint injuries. To solve this problem, we have to start from the beginning. Osteoarthritis is a common chronic degenerative joint disease. Nearly 220 million people worldwide suffer from arthritis pain.

Osteoarthritis is a degenerative injury of articular cartilage, which mainly includes destruction of articular cartilage, subchondral bone sclerosis and synovial hyperplasia. There are many causes, such as aging, obesity, fatigue damage, trauma, congenital joint deformities, joint deformities, etc.

Osteoarthritis mainly occurs after middle age. Among people aged 40-70 years, the incidence rate in women is higher than that in men. After the age of 70, the incidence rate is equal in both sexes. The clinical manifestations of osteoarthritis are joint pain, joint stiffness, and in severe cases, loss of joint function. By 2021, osteoarthritis will become the fourth most disabling disease.

Since the hyaline cartilage tissue on the surface of bone joints has no nerves and blood vessels, the cartilage has poor self-repair and regeneration capabilities. Once damaged, it is difficult to recover on its own. At present, the clinical treatments for osteoarthritis mainly include non-drug therapies, such as targeted exercise, heat therapy, cold therapy, insoles, acupuncture, etc.; drug therapy and surgical treatment, but these can only relieve pain to a certain extent. Improving symptoms, delaying the disease, and correcting deformities cannot completely delay the progression of the disease. Autologous chondrocyte transplantation has been successfully used to repair cartilage, but chondrocytes cultured in vitro show differentiation, which reduces the expression of chondrocyte-specific genes, thereby affecting the therapeutic effect.

In recent years, new treatments for osteoarthritis based on stem cells have attracted increasing attention. Mesenchymal stem cells have the potential of self-renewal and directed differentiation, can repair cartilage tissue, inhibit the secretion of inflammatory factors and homing properties of chondrocytes, and are very potential cells for the gradual treatment of osteoarthritis.

Mechanism of action of mesenchymal stem cells

Mesenchymal stem cells are found in various tissues, such as bone marrow, umbilical cord, placenta, tendon, periodontal tissue, and adipose tissue. In 2006, the International Society for Cell Therapy ( ISCT ) defined mesenchymal stem cells using three criteria:

1. Can be attached to plastic surfaces and grow;
2. Expresses CD105, CD73 and CD90 and lacks CD45, CD34, CD14 or CD11b, CD79a or CD19 and HLA-DR surface molecules;
3. After induction in vitro, mesenchymal stem cells can differentiate into osteoblasts, adipocytes and chondrocytes.

In addition to their differentiation potential, mesenchymal stem cells also express and secrete a variety of enzymes and secrete a variety of trophic factors involved in paracrine activities, including growth factors, cytokines, and chemokines, which nourish cells by activating and angiogenic pathways. cartilage .

Mesenchymal stem cells also participate in local immune regulation mechanisms, which can inhibit the proliferation of T cells, the maturation of dendritic cells, the activation and proliferation of B cells and the secretion of antibodies, thus affecting the polarization of macrophages and the differentiation of antibody-secreting cells. Eliminates rejection and the spread of disease. Among them, the polarization of macrophages is stimulated by INF-γ and IL-1β, which convert macrophages from pro-inflammatory ( M1 ) to anti-inflammatory ( M2 ); moreover, mesenchymal stem cells can also interact with macrophages. Phages interact with each other to inhibit macrophage activation and secretion of IL-1β, TGF-α and other inflammatory factors.

Of course, the regulatory functions of mesenchymal stem cells may vary depending on the individual, species, tissue source, culture conditions, and activation status. The homing effect of mesenchymal stem cells can migrate to the site of cartilage ischemia or damage under the influence of the microenvironment in the body. In addition, mesenchymal stem cells can also repair and reconstruct damaged tissues by secreting growth factors, cytokines and extracellular matrix. Studies have shown that cytokines secreted by mesenchymal stem cells can target synovium and chondrocytes, where they can regulate anabolic and catabolic factors and induce the expression of anti-inflammatory and chondrogenic molecules.

With the deepening of research, most recent studies have shown that mesenchymal stem cells mainly regulate local inflammation, cell apoptosis and proliferation through paracrine mechanisms, rather than directly differentiating into chondrocytes to participate in tissue repair . The researchers pointed out that endogenous mesenchymal stem cells maintain the health of tissues through the resource reservoir of cell repair and the outpost of immune regulation. In activating the repair response, the transmission of paracrine signals of mesenchymal stem cells is more important than differentiation. . This means that mesenchymal stem cells are not used to replace damaged cartilage, but to coordinate and enhance the repair response .

Repair mechanism of MSC in bone and joint injuries

clinical research

1. Local intra-articular mesenchymal stem cell injection and mixed injection

Mixed injection refers to mixing growth factors, cytokines and scaffolds with mesenchymal stem cells to improve the efficacy. Commonly used stents include polymers such as hemagglutinin and fibrin gel, and nutrient-rich body fluids such as high-concentration platelet plasma ( PRP ). Among them, there are many clinical studies on injecting mesenchymal stem cells ( MSCs )/PRP mixture into the joint cavity. PRP is an autologous tissue that is rich in cartilage-derived growth factors ( such as TGF-β and platelet-derived growth factor ) and can be used as a tissue source to treat damaged cartilage. The PRP composite scaffold has high osteogenic induction activity and can promote bone healing . PRP combined with MSCs composed of adipose mesenchymal stem cells and adipose tissue vascular matrix can create a suitable microenvironment to promote blood supply, reduce local inflammatory response, promote the synthesis of cartilage mechanism, and improve the treatment of knee joints with mesenchymal stem cells. Therapeutic effect of arthritis. At present, problems with PRP still lie in the variability of its preparation method and the number of expressed bioactive factors . Some growth factors ( such as vascular endothelial growth factor ) secreted by RPR may have adverse effects on joints and mesenchymal stem cells.

With increasing evidence of the successful use of stem cell technology in animals and in vitro experiments, transplantation of stem cells to treat osteoarthritis also shows potential to regenerate cartilage. To date, nearly 80 relevant clinical studies have been registered on Clinicaltrail.gov, some of which have completed clinical trials and preliminary assessments of safety and effectiveness. According to existing research results, mesenchymal stem cell therapy ( derived from bone marrow, fat and umbilical cord ) therapy has shown very good efficacy in the treatment of osteoarthritis and may replace traditional therapies in the future.

2. Bone marrow mesenchymal stem cells

Bone marrow mesenchymal stem cells are the earliest and most common effective source used to treat osteoarthritis, and have achieved promising results in clinical repair of knee joint cartilage. In 2008, a study reported a case of using bone marrow mesenchymal stem cells to treat severe knee osteoarthritis. During injection, bone marrow mesenchymal stem cells are combined with 10% platelet lysate and 10ng dexamethasone to stimulate cartilage. Six months after the injection, MRI showed significant growth of articular cartilage and menisci, and a significant reduction in pain. Positive results have been achieved with a single injection of bone marrow mesenchymal stem cells into the joint cavity, even when adjuvant analgesics, anti-inflammatory drugs, or immunosuppressants are not applicable. Studies have shown that bone marrow mesenchymal stem cell transplantation is more effective than autologous chondrocyte therapy and has relatively fewer complications. Although the safety and effectiveness of bone marrow mesenchymal stem cells have been widely confirmed, it is difficult to obtain a sufficient amount of primary stem cells in actual clinical applications, which is largely affected by the age of the donor . Different levels of trauma and differentiation .

3. Adipose mesenchymal stem cells

Adipose mesenchymal stem cells are also one of the effective sources for the treatment of osteoarthritis. Usually obtained through liposuction or infrapatellar fat pad extraction, the liposomes are centrifuged and dissolved by adding collagenase I to prepare concentrated mesenchymal stem cells. It has been reported that intra-articular injection of 1.0x10 lipid mesenchymal stem cells can significantly improve knee joint pain and function without adverse events. Patients who received the mid-dose ( 5.0x10 7 ) showed improvement in clinical indicators, while most patients in the low-dose group ( 1.0x10 7 ) did not show improvement in clinical indicators. These results indicate that the efficacy of intra-articular injection of mesenchymal stem cells is significantly dose-related , and further clinical trials are needed to prove the long-term safety and clinical advantages of high-dose injection. Compared with bone marrow stem cells, adipose mesenchymal stem cells have a lower potential to generate cartilage, and their ability to generate cartilage-specific matrix proteins and expression of type I collagen genes are also relatively low. Therefore, the stimulation of the cartilage regeneration potential of adipose mesenchymal stem cells needs to be further optimized and improved.

Problems with mesenchymal stem cell transplantation

Although there is a lot of relevant evidence proving the ability of mesenchymal stem cells to treat osteoarthritis, existing problems cannot be ignored.

1. The number of viable stem cells after injection is extremely low , making it impossible to predict long-lasting improvements and cell-cell interactions, and whether sufficient cell stores can be maintained to achieve the desired therapeutic effect;
2. Donor suitability may be another important challenge, as mesenchymal stem cells isolated from old or unhealthy donors have been found to have reduced performance and proliferation ;
3. Before transplantation, long time of ex vivo expansion of mesenchymal stem cells may lead to induced senescence, loss of proliferation ability and reduced differentiation ability (especially population doubling exceeding 10-20 times);
4. Since calcification after chondrogenic induction is genetically programmed as part of the normal endochondral osteogenesis process, maintaining differentiated mesenchymal stem cells in a chondrogenic phenotype and organizing their calcification to extend toward an osteogenic phenotype is also an issue that needs to be addressed;
5. Mesenchymal stem cells are sensitive to some "environmental response" factors and carry out specific modification behaviors in response to trace amounts of unknown substances in the microenvironment. Although this response is often exploited in regenerative medicine, mesenchymal stem cell responses can be negatively impacted in the context of diseased joints. It has been reported that human adipose mesenchymal cells convert into a pro-inflammatory secretome and enhance the inflammatory response after reacting with tumor necrosis factor (TNF).

Mesenchymal stem cell exosomes

Because of some of the problems of stem cell transplantation mentioned above, the discovery of mesenchymal stem cell exosomes is expected to avoid these risks.

As mentioned earlier, more and more studies have shown that the real role of injecting mesenchymal stem cells in the treatment of osteoarthritis is the biomolecules secreted by the paracrine system of stem cells, which regulate the microenvironment of the affected area and activate the original stem cells to repair damaged tissues. Stem cell exosomes are also attracting more and more attention. Exosomes are a soluble biological medium isolated from mesenchymal stem cell culture medium. Exosomes are produced under pathological and physiological conditions, and they are the main mediators of intercellular communication by transferring mRNA, lipids, siRNA, proteins, miRNA and ribosomal RNA to adjacent or distant cells. Studies have found that mesenchymal stem cell exosomes can protect chondrocytes from apoptosis and block giant cell proliferation by increasing chondrocyte markers ( such as type II collagen and aggrecan ), reducing inflammatory markers ( iNOS ), and protecting chondrocytes from apoptosis. Phages are activated. Mesenchymal stem cell exosomes can attenuate osteoarthritis by stimulating chondrocyte migration and proliferation .

Injecting mesenchymal stem cell exosomes has many similar biological effects to injecting intact stem cells , and has significant advantages over injecting intact mesenchymal stem cells, such as small size, low immunogenicity, and elimination of direct cell Injection procedure issues. Exosomes are considered to be powerful intercellular messengers that not only mediate pathological processes but also maintain tissue homeostasis and regulate physiological functions in a variety of therapeutic approaches. Although there have been several studies using stem cell-derived exosomes to treat joint injuries and osteoarthritis, conclusive evidence is still lacking. As a new cell-free treatment for osteoarthritis and joint injuries, a large number of clinical trials are needed to confirm its effectiveness.

Although osteoarthritis is very common, it seriously affects people's lives. Traditional treatment methods are difficult to fundamentally solve the pain, and can also cause a series of side effects and cause significant harm to patients. With in-depth research on mesenchymal stem cells and stem cell exosomes, new therapies based on mesenchymal stem cells have gradually shown advantages in the treatment of osteoarthritis.

postscript

Intra-articular injection of mesenchymal stem cells reduces pain, improves function and significantly increases cartilage volume. Of course, this new therapy still requires a large number of clinical trials to obtain a higher level of evidence and to fully standardize and optimize treatment.