Knowledge Points of Stem Cells

Today, with the development of life sciences, people's awareness of health and beauty is becoming stronger and stronger! To say that the hottest cell technology is still stem cells! Not only does it have a place in medical treatment of difficult and miscellaneous diseases, but also many celebrities and dignitaries use stem cells for health care and anti-aging!

What are stem cells? Where are stem cells found in the human body?

Stem cells are primitive cells with self-replication, multidirectional differentiation and homing potential . They are the origin cells of the body and the ancestor cells that form various tissues and organs of the human body. Just like the trunk of a tree, it can grow branches, leaves, flowers and fruits. Nowadays, scientists have successfully isolated stem cells from many organs or tissues, including retinal stem cells, pancreatic stem cells, and osteoblast stem cells. Studies have shown that stem cells exist not only in embryos, but also in adults, and corresponding stem cells can be isolated from umbilical cord blood, umbilical cord, placenta, bone marrow, fat, blood and other tissues.

Where do stem cells come from?

During the process of cell differentiation, due to the uneven distribution of differentiation-regulating proteins in the cytoplasm, a daughter cell irreversibly moves towards the end of differentiation and becomes a functionally specialized differentiated cell, until it completely loses the ability to divide again and eventually senescence and death. In order to make up for this deficiency, the body retains a part of undifferentiated primitive cells, which keeps the characteristics of the parents. These retained undifferentiated primitive cells are called stem cells. Once physiologically required, these stem cells can divide according to the developmental pathway to produce differentiated cells.

What are the characteristics of stem cells?

(1) Infinite proliferation and division;(2) Stem cells can divide continuously for several generations, and can also be in a resting state for a long time;(3) Regulation by internal signals;(4) Two ways of stem cell division: differentiate cells with differentiation ability, still maintain parental characteristics, and stand by as stem cells; irreversibly terminally differentiate, lose differentiation ability, and eventually die of aging.

What is the job of stem cells?

The task of stem cells is to generate a large number of working cells through its unlimited replication characteristics, so that human organs can work normally. Scientists summarize the five major tasks of stem cells, referred to as 5R:

Replace replace or supplement

Repair repair or repair

Regenerate tissue and organ regeneration

Restore Restoration or restoration of vital functions

Regression of cancer cells

Theoretically, if 5R can function properly, the body will not get sick, age, or even die.

What effects do stem cells have on the human body?

(1) Enhance the body's immune system, adjust the growth factor index, promote rapid wound healing and avoid scarring;

(2) Promote the regeneration of organ tissue cells, rejuvenate organs, and delay organ aging;

(3) Improve sleep quality and improve sub-health;

(4) Protect the liver and treat liver fibrosis and cirrhosis;

(5) Promote metabolism;

(6) Enhance physical fitness and energy and make the body full of vitality;

(7) Promote the growth of cardiomyocytes, improve cardiac function endurance, and prevent heart disease and stroke;

(8) Stabilize blood pressure and balance cholesterol;

(9) Improve skin and problematic skin, restore skin luster, smoothness and elasticity, reduce wrinkles, and rejuvenate the face;

(10) It can enhance sexual ability and improve the quality of sexual life;

(11) Improve the ability of the motor system and improve osteoporosis and waist and leg pain;

(12) Restore nervous system function, improve memory, and prevent Parkinson’s disease, Alzheimer’s disease, etc.

Causes and manifestations of aging?

(1) The root cause of human aging and the appearance of wrinkles is the aging and reduction of cells, which is basically caused by the aging of stem cells. (2) The core of smooth, moist and elastic skin is collagen, elastin fibers and hyaluronic acid. The former two are related to skin thickness and elasticity, while the latter is closely related to skin moisture content. Collagen, elastic fibers and hyaluronic acid are synthesized by cells in the skin. Once the vitality of the cells is reduced, these synthesis will be reduced, and the skin will become inelastic, moisture-free, loose and dry. (3) Stem cells, as seed cells used to replace various tissue cells, are the production products of human cells. Aging of stem cell populations severely weakens their ability to proliferate and differentiate. (4) The ability to replenish new cells is insufficient, and aging cells cannot be replaced in time, resulting in a decline in body function and people getting older every day. And our skin, because the aging of skin stem cells cannot be renewed in time, the cells cannot synthesize enough collagen, elastic fibers and hyaluronic acid, the skin slowly begins to age, so you have wrinkles, spots, etc., and gradually lose youth.

Why stem cell therapy can fight aging?

Throughout a person's life, cells in the body are always in the process of replacing aging and degenerated cells with new cells. When the cell renewal rate is lower than the cell aging rate, insufficient renewal occurs and the body will age. It manifests as a decline in systemic system functions, slow metabolism, and the appearance of aging. The cells in the body that can play a role in renewal are stem cells, and the source of aging is the insufficient number of stem cells. Stem cell transplantation therapy is to replenish the body's deficient stem cells and help the body quickly renew and replace aging cells, thereby making the body young and full of vitality.

What is the relationship between anti-aging and stem cell quantity?

When a person is born, the number of human body cells is about 3 trillion. Among them, there are about 6 billion stem cells. This is the time when the number of stem cells is the largest in life, and it is also the time when they grow fastest. As we age, the number of stem cells begins to decline. By the age of 25, the number of somatic cells in the human body has reached about 60 trillion, while the number of stem cells is only about 1 billion. The human body stops growing and begins to gradually age. By the age of 50, the number of body cells is still about 60 trillion, but the number of stem cells is only about 300 million, and human aging is accelerated. The functions of various organs decline and the incidence of major diseases increases. Therefore, human aging is directly related to the number of stem cells.

What role do stem cells play in anti-aging?

improve skin

Stem cells can migrate to the epidermis and transform into skin stem cells. An early skin stem cell can produce 4 million epidermal cells, providing a sufficient and good source for cell renewal of the skin system. The new cells have strong metabolic capacity and can discharge metabolic waste in a timely manner, preventing pigment from depositing in the skin, thereby inhibiting and reducing the formation of spots. The newly differentiated young cells have good water retention, which is enough to restore aging skin to be delicate and smooth. At the same time, it synthesizes a large amount of collagen and elastic fibers, restores the collapsed network structure, restores skin elasticity, reduces wrinkles, and fundamentally improves the quality of the skin system.

Slimming

Stem cells cultured in vitro and then reinfused into the human body can improve the state renewal of cells in the body, thereby enhancing cell activity, improving the body's ability to metabolize fat, reducing the fat content in cells, reducing the volume of fat cells, and significantly reducing body weight. This can achieve the effect of slimming down, effectively reduce the concentration of total cholesterol and triglycerides in the blood, and prevent the occurrence of diseases. Nowadays, scientists have successfully isolated stem cells from many organs or tissues, including retinal stem cells, pancreatic stem cells, and osteoblast stem cells. Studies have shown that stem cells exist not only in embryos, but also in adults, and corresponding stem cells can be isolated from umbilical cord blood, umbilical cord, placenta, bone marrow, fat, blood and other tissues.

Maintain ovaries

Stem cells migrate to the ovary along with the blood circulation, and then differentiate to produce a sufficient amount of new ovarian cells to supplement the number of ovarian cells and maintain the normal shape of the ovary, thereby preventing ovarian atrophy and deformation. In addition, newborn ovarian cells can respond to pituitary gonadotropin in a timely and correct manner, secrete sufficient estrogen, and keep hormone levels in the body in a balanced state. The reinfused stem cells can improve women's various troubles caused by ovarian function decline, eliminate various discomfort symptoms of menopause, restore menstruation to women who have premature menopause or normal menopause, delay menopause, thereby inhibiting aging, and make female friends Regain the beauty of youth and health.

Prostate health care, sexual function improvement and enhancement

Stem cells are the source cells for rebuilding and restoring the structure and function of tissues and organs. While stem cells repair the aging and degeneration of various organs in the body, they also significantly regenerate and repair the aging and degeneration of the reproductive system, restoring and strengthening male sexual function. Stem cell health care can significantly improve the sexual function of most men, with strong and lasting erections, and significant improvements in sexual desire, sexual frequency and sexual life satisfaction.

The effect of stem cells to repair the aging and degeneration of the reproductive system and restore function is essentially different from the replacement use of male hormones and Viagra, and can restore its structure and function for a long time. The improvement and improvement of sexual function is related to the regeneration of the reproductive system structure by stem cells and the overall rejuvenation and vitality of the body. It is a healthy and ideal health care method for restoring sexual function.

In addition, stem cells can also eliminate prostatitis, remove toxins from the body, strengthen the immune system, prevent viruses from entering, quickly eliminate symptoms of urinary discomfort such as frequent urination, urgency, and painful urination, and improve prostate lesions, such as prostatic hypertrophy, prostatic hyperplasia, and prostatitis , and continue to maintain male prostate health and smooth urination.

What is Stem Cell Technology?

Stem cell technology refers to the process of cultivating stem cells in vitro, isolating, purifying, amplifying, and directional induction to breed new, normal, or even younger cells in vitro, and finally inject them back into the human body to achieve a youthful appearance. Chemical, prevention of chronic diseases, anti-aging, anti-cancer and other purposes.

Is Stem Cell Therapy Safe?

In 2020, the State Food and Drug Administration has approved more than 20 stem cell application transformation and clinical research projects. In stem cell research, preclinical safety experiments have been completed, including acute toxicity, long-term toxicity, tumorigenicity, teratogenicity, local irritation, fever and immunotoxicity tests, and the results show that it is safe and non-toxic. Because stem cells are undifferentiated and immature cells, their surface antigen expression is very weak, and it is extremely difficult for the patient's own immune system to recognize them. Therefore, stem cell therapy will not cause immune rejection and allergic reactions, and is very safe.

Price of MSC drugs marketed around the world

One of the important value manifestations of stem cells is the application in disease treatment. Professor Thomas C. Sudhof, winner of the Nobel Prize in Physiology or Medicine, once said, "We can control diseases, and stem cells are a very good treatment method." Stem cell research will bring new hope for problems that cannot be solved by traditional medical treatment. "

Internationally, the United States, South Korea, Japan, and the European Union have all approved stem cell therapy products on the market, and stem cell therapy for diseases is becoming a more widespread reality.

According to incomplete statistics, there are 18 mesenchymal stem cell products that have been approved for marketing in the world, and 10 of them meet the definition of drugs.

A mesenchymal stem cell drug that may be approved recently

March 7, 2023 - Mesoblast Limite, a global leader in allogeneic cellular medicines for inflammatory diseases, announces that the U.S. Food and Drug Administration (FDA) Office of Therapeutic Products ( OTP ) has accepted the company's resubmitted Biologics License Application ( BLA ), the mesenchymal stem cell drug-remestemcel-L, for the treatment of children with steroid-refractory acute graft-versus-host disease ( SR-aGVHD).

The FDA considered the company's resupplement submission complete and set a Prescription Drug User Fee Act ( PDUFA ) target date of August 2, 2023.

remestemcel-L is an allogeneic donated bone marrow-derived mesenchymal stem cell ( MSC ), which has immunomodulatory effects, can down-regulate the production of pro-inflammatory cytokines and increase the production of anti-inflammatory cytokines to fight against various diseases inflammatory process.

Cell Therapy Prices

When it comes to cell drugs, is it easy for everyone to think of the 1.2 million injection of CAR-T, and the price of mesenchymal stem cell drugs? From low to high, let's take a look at how the foreign mesenchymal stem cell drugs that have been approved for marketing are priced. for reference only.

Indications for severe limb ischemia, stempeucel is priced at 150,000, and INR 2,200. In 2020, the Indian Drug Administration officially approved stempeucel for the treatment of severe limb defects caused by thromboangiitis obliterans. Stempeucel is the first in India The official selling price of this stem cell drug, which has not yet been found, is the cost price set when it was conditionally approved in 2016.

Cartistem is indicated for degenerative arthritis, and the price for a single treatment is up to 10 million won, or about 7,600 US dollars. Generally, it is treated 1 to 3 times. In 2012, the Korean Food and Drug Administration approved cartistem for the treatment of degenerative or repetitive trauma. Knee cartilage defects caused by osteoarthritis patients, Cartistem is the only umbilical cord blood-derived mesenchymal stem cell drug in the world and the only pre-charged stem cell drug in Korea that has completed phase III clinical trials before it goes on the market. Cartistem is also in the Korean market Mesenchymal stem cells with the best performance, the drug has achieved a sales revenue of 88.5 billion won in the ten years since its launch.

cuepistem indication Cronding, a treatment needs more than 13 million won about 10,000 US dollars, in 2012 cuepistem obtained the Korean Food and Drug Administration, conditional approval for the treatment of Trohn's disease, complex perianal leakage, cuepistem It is the first adipose-derived mesenchymal stem cell drug in the world and the only mesenchymal stem cell therapy included in the national health insurance in South Korea. Patients only need to pay 10% of the drug cost.

Cellgram-AMI is indicated for acute myocardial infarction, and a single treatment requires 18 million won or about 13,700 US dollars. In 2011, the Korean Food and Drug Administration approved Cellgram-AMI for the treatment of acute myocardial infarction. Cellgram-AMI is considered the first in Korea and even in the world. 1 stem cell drug, the cumulative sales of Cellgram-AMI will reach 17.1 billion won by the end of 2021, which is equivalent to treating 950 patients.

NeuroNATA-R is indicated for ALS, and a single treatment requires 25 million won, about 19,600 U.S. dollars. In 2014, NeuroNATA-R received conditional approval from the Korean Food and Drug Administration for the treatment of ALS. motor nerves. In 2021, a phase III clinical trial will evaluate the long-term safety and efficacy of NeuroNATA-R in South Korea, and it is expected to recruit more than 300 patients with ALS throughout the year.

Alofisel is indicated for Crohn's disease. The price of Alofisel in the EU is 54,000 yuan, and the price in Japan is 5.62 million yen. In 2018 and 2021, Alofisel was first approved by the European Medicines Agency and the Ministry of Health, Labor and Welfare of Japan. For the treatment of complex perianal leakage in patients with Crohn's disease, Alofisel will start in 2019 and adopt value-based pricing in Europe. If patients do not improve, they will bear part or even all of the costs.

Stemirac indication Spinal cord injury, priced at 14.95 million yen, estimated to be about 110,000 US dollars, in 2018, according to a single-group clinical trial involving 13 subjects, stemirac was approved by the Japanese Ministry of Health, Labor and Welfare with special conditions, provided that It must prove its effectiveness and safety within 7 years after approval. In 2019, stemirac was included in the NHI drug list, that is, it entered the medical insurance list.

TEMcell indication Graft-versus-host disease, more than 860,000 yen per bag, 8 generations a course of treatment, 2-3 courses of treatment for adult patients is expected to be about 100,000 to 150,000 US dollars. The predecessor of temcell is prochymal of Osiris company in the United States, which was launched in the United States in 2010 The FDA approved it as an orphan drug for the treatment of type 1 diabetes.

Pyochymal indications for acute graft-versus-host disease, priced at $200,000 for a course of 4 doses, sold to Masoblast in Australia in 2012, and approved for marketing in Canada and New Zealand for the treatment of acute graft-versus-host disease, In 2015, masoblast cooperated with JCR Corporation of Japan and renamed it temcell, which was listed in Japan and included in the NHI drug list. In JCR's financial report, temcell's sales revenue has increased from 600 million yen in 2016 to 3.5 billion yen in 2021, and it is currently the mesenchymal stem cell drug with the highest annual sales.

To sum up, the most expensive mesenchymal stem cell drug is Pyochymal, which costs more than 1 million RMB. Its close relative, temsell, is priced at about 700,000 to 1 million RMB after it is launched in Japan. If you don’t consider stempeucel, which has no official price, the cheapest mesenchymal stem cell Mesenchymal stem cell drug treatment costs about 50,000 yuan a time.

In my country, stem cells are regulated according to the dual-track system of drug and technology management. In recent years, the clinical research projects of mesenchymal stem cells that have been filed for record are also increasing. More people benefit from the development of regenerative medicine.

Finally, it should be emphasized that as of now, no stem cell drug for cancer treatment in my country has been approved for marketing. Stem cell therapies advertised on the market are usually imported from South Korea or Japan, because these two countries have a large number of approved stem cell drugs.

Stem cell technology "revitalizes" senescent cells and rejuvenates human senescent cells

Human aging is an inevitable natural law, but a recent report published in "Nature" pointed out that scientists at the Stanford University School of Medicine have used stem cell technology to rejuvenate human aging cells and reverse the effects of aging on cells.

The study found that inducing aged cells to express these proteins transiently in a lab dish reversed many of the molecular hallmarks of aging and made treated cells nearly indistinguishable from younger cells.

By comparing the methyl groups that mark cell age, treated aged cells were on average 1.5 to 3.5 years younger than untreated aged cells, and blood vessel cells were even up to 7.5 years younger .

01. Expression of Yamanaka factors found to reverse aging

To test whether this therapy could also be used for more general anti-aging purposes, the researchers coaxed muscle stem cells from aged mice to express a specific set of proteins that are essential for embryonic development in the short term. They found that when transplanted back, the old mice regained their youthful strength.

Stem cells are encouraged to express a group of proteins called Yamanaka factors that play a crucial role in converting adult cells into induced pluripotent stem cells (iPS cells) . These cells have the potential to differentiate into virtually any human cell type, making them an important area of ​​drug discovery and regenerative medicine research.

The Stanford team demonstrated that in inducing cells extracted from older people to briefly express Yamanaka factors, many features of senescent cells were reversed, resulting in little difference from young cells.

02. Reversing aging gives mice 20% longer lifespan

A group of researchers on the team made iPS cells by exposing adult iPS cells to the body.

Over a two-week period, adult cells are exposed to short-lived RNA messages that encode instructions for making Yamanaka proteins. Over time, the protein has the effect of reversing the timeline of a cell's development, forcing it to revert to an embryo-like state of pluripotent cells.

In the process, the cells not only released any memory of their previous identities, but also returned to their youthful state . They accomplished this translation by swabbing the DNA to remove molecular tags that not only differentiate skin cells from heart muscle cells, but also other tags that accumulate as the cells age.

Additionally, to find out whether human cells would function in the same way, the Stanford researchers designed an experiment in which they used messenger RNA to transiently express the four Yamanaka factors, along with two other proteins, in blood vessel and skin cells of older adults. Because messenger RNA is rapidly degraded within cells, the duration of exposure to these factors can be controlled.

The gene expression patterns of these treated human cells were then analyzed and compared to gene expression in control cells, also obtained from the older population, and to untreated cells obtained from the younger population.

The results showed that treated cells showed signs of age reversal after four days of exposure and had lower levels of genes associated with various aging pathways compared with untreated senescent cells. The treated aged cells were more similar to young cells in terms of gene expression , giving prematurely aged mice a 20 percent increase in lifespan.

The researchers analyzed the cells for their methyl groups, which can indicate age chronologically. Using this approach, it was found that treated cells appeared to be on average 1.5 to 3.5 years younger than untreated old cells, and blood vessel cells were even up to 7.5 years younger. The team is pleased that this marks an important step in the field of anti-aging research.

Autologous or allogeneic stem cells?

Mesenchymal stem cells (MSCs) have been the subject of countless clinical studies involving pathologies ranging from Crohn's disease to graft-versus-host disease (GVHD).

Mesenchymal stem cell-based therapies are already available to treat a range of diseases or medical conditions. Autologous or allogeneic mesenchymal stem cells obtained from oneself or a donor each have advantages and disadvantages in medical practice.

Mesenchymal stem cells (MSCs) can differentiate into mesoderm-derived cell lineages such as osteocytes, adipocytes, and chondrocytes.

150 years ago, German pathologist Cohnheim first proposed the existence of mesenchymal stem cells in bone marrow (BM). Scientists Friedenstein et al. originally described and characterized MSCs as discrete "fibroblast" colonies of BM in the 1970s.

It is now known that such cells are located in many types of adult tissues, including bone marrow, adipose tissue (AT), peripheral blood, and human embryonic tissues such as fetal liver, fetal bone marrow, aorta-gonads-mesonephros, and yolk sac, as well as Various neonatal birth-related tissues, including placenta, umbilical cord (UC), Wharton's Jelly (WJ), and umbilical cord blood. MSCs can also originate from perivascular or mural cells, known as pericytes, in almost all vascular tissues.

Due to different tissue-specific properties, mesenchymal stem cells from different tissues exhibit different phenotypic properties and functional behaviors. In the late 1980s, scientist Kaplan coined the name "mesenchymal stem cells" based on several key facts.

Advantages and Disadvantages of Autologous and Allogeneic MSCs

Clinical applications of autologous and allogeneic MSCs have enabled the treatment of a range of diseases or conditions. Autologous mesenchymal stem cells are easy to obtain and there is no immune rejection after infusion.

However, autologous MSCs require weeks for isolation, ex vivo expansion, and release, and patient-derived autologous MSCs may be the source of systemic disease.

Allogeneic MSCs offer several advantages, such as donor selection, diverse sources, low immunogenicity, and ready availability.Allogeneic mesenchymal stem cells may also be immunogenic, and such cells can induce immune memory responses under appropriate conditions, although mesenchymal stem cells are considered to be immunoprivileged or immunocompromised.

An in vivo study evaluating the clinical response to repeated intra-articular injections of autologous and allogeneic MSCs found significant adverse joint responses to allogeneic MSCs after the second injection, suggesting adaptation to injected allogeneic MSCs. immune response, but not autologous mesenchymal stem cells .

In contrast, another study observed that implanted allogeneic MSCs expressed high levels of MHC-Ia and MHC-II in a rat model of myocardial infarction (MI) 14 days after cell implantation, and The therapeutic effect was lost within 5 months after cell engraftment, which also indicates the transition from immune privilege to an immunogenic state after differentiation of MSCs.

Currently, allogeneic mesenchymal stem cell therapies are increasing in clinical translation, and these cells have been shown to be clinically safe and effective. To minimize any potential anti-donor immune response, scientists have proposed several strategies, including the use of immunosuppressive drugs.

However, the potential risks and limitations of using autologous versus allogeneic MSCs for therapeutic applications remain controversial, such as the potential impact of donor-to-donor heterogeneity. Overall, allogeneic and autologous MSCs have their own advantages and disadvantages in preclinical and clinical practice.

Therapeutic effects of autologous MSCs and allogeneic MSCs

Autologous and allogeneic mesenchymal stem cells have their own advantages and disadvantages. On an individual treatment basis, the clinical application of autologous or allogeneic mesenchymal stem cells needs to be designed to maximize their therapeutic activity while maximizing their therapeutic activity. Reduce its potential side effects.

Clinical trials have shown that the effectiveness of treatments using autologous versus allogeneic mesenchymal stem cells is inconclusive, but treatment with such cells appears to be unquestionably safe. An early clinical study reports that intramyocardial or intracoronary autologous bone marrow mesenchymal stem cell therapy is safe and effective for chronic severe dilated cardiomyopathy (DCM), demonstrating improved left ventricular function and reduced scarring in these patients.

A randomized, double-blind, placebo-controlled clinical trial reports the safety and efficacy of allogeneic bone marrow-derived mesenchymal stem cells in the treatment of acute myocardial infarction, showing left ventricular ejection in patients treated with mesenchymal stem cells. Scores and refactoring were improved.

As described above, autologous or allogeneic MSC treatment improves left ventricular ejection fraction, reduces scar size, reverses ventricular remodeling, and triggers cells to secrete paracrine factors.

Mesenchymal stem cells also show potential in treating diabetes and diabetic complications. Both autologous and allogeneic MSCs are widely used to treat individuals with type 1 and type 2 diabetes (T1DM and T2DM). Autologous bone marrow-derived mesenchymal stem cells have shown therapeutic potential in T2DM with critical limb ischemia and foot ulcers and lower limb bullous diabetes.

A pilot clinical trial also evaluated the use of autologous bone marrow mesenchymal stem cells to treat diabetic retinopathy, and this study demonstrates autologous mesenchymal stem cells as a potentially safe and effective treatment option for diabetic retinopathy. Laboratory parameters and clinical trial data from the trial showed significant decreases from baseline in fasting glucose and serum C-reactive protein levels at 1, 3, and 6 months of follow-up, and in best-corrected visual acuity after 3 and 6 months, respectively. Significantly increased.

Specific therapeutic effects of mesenchymal stem cells from different sources

MSC sources are becoming important in preclinical and clinical applications. Due to the different tissue-specific properties of MSCs and the diversity of special tissue microenvironments associated with MSCs, MSCs obtained from different types of tissues have different functional behaviors.

There are important differences in the characteristics of BM ( bone marrow )-derived MSCs and AT (adipose tissue)-derived MSCs reported in previous studies . Importantly, BM-derived MSCs exhibited higher osteoblastic differentiation potential and lower adipogenic potential compared with AT-derived MSCs.

In an in vivo study, UC (umbilical cord)-derived MSC showed the strongest therapeutic efficacy among three types of MSC in regulating fasting blood glucose in T2DM mice, followed by dental pulp-derived MSC, which showed moderate efficacy, However, pulp-derived MSC had the lowest efficacy.

In addition, although mesenchymal stem cells from different sources have similar functional properties, such as anti-inflammatory effects, the paracrine effects of mesenchymal stem cells from different sources behave differently. Previous studies have shown that extracellular vesicles (EVs) secreted by MSCs from different sources have specific functions and therapeutic effects, thus reflecting paracrine differences between MSCs from different tissue sources. For example, EVs secreted by human bone marrow-derived mesenchymal stem cells can promote cartilage regeneration and osteoarthritis in vitro, suggesting that EVs from bone marrow-derived mesenchymal stem cells have specific osteoinductive potential. In summary, further work is needed to identify optimal sources of MSCs as a priority for their safe and effective clinical application, while acknowledging that MSCs from different sources have different functional properties in vitro.

In summary, the plasticity and functional heterogeneity of mesenchymal stem cells may pose potential problems for safe and effective mesenchymal stem cell-based treatments in clinical applications. Acknowledging the link between the biological properties of MSCs and MSC-related microenvironmental factors will facilitate a better understanding of the contribution of MSCs to their medical practice, whether promising or uncertain. As of March 2021, nearly 1,000 clinical trials have been registered on ClinicalTrials.gov using autologous and allogeneic MSCs to treat a variety of human diseases and medical conditions. Available clinical data suggest that the therapeutic benefits of using autologous or allogeneic MSCs as better options are inconclusive.