Stem cells are undifferentiated, immature cells with the capacity for self-renewal and multi-lineage differentiation. They are like the "universal seeds" of life, capable, under specific conditions, of differentiating into various cell types, offering boundless possibilities for tissue repair and regeneration. Stem cells can be classified by potency into totipotent, pluripotent, and multipotent stem cells.

Mesenchymal stem cells (MSCs) are multipotent stem cells that possess self-renewal and multi-directional differentiation abilities. They can be isolated from multiple tissues, such as bone marrow, adipose tissue, and umbilical cord. MSCs exhibit a wide range of biological functions, including anti-inflammation, anti-apoptosis, neuroprotection, angiogenesis, and immune modulation. These tiny cells hold enormous potential and bring new hope for human health.

Four Core Functions of Mesenchymal Stem Cells

1. Tissue Regeneration and Organ Repair

      As multipotent cells, MSCs cannot develop into a complete organism, but they have the potential to differentiate into many cell types in the human body. These derived cells can both replace and repair damaged cells, as well as stimulate endogenous stem cells to collectively accomplish tissue regeneration.

Under appropriate induction, mesenchymal stem cells can differentiate into a variety of cell types within the body.

Skeletal System:

For fracture patients, MSCs can promote callus formation and accelerate fracture healing. They can differentiate into osteoblasts, secrete bone matrix components, and increase bone mineral density and strength [1].

In joint diseases such as osteoarthritis, MSCs can repair damaged articular cartilage, alleviate pain, and improve joint function. By secreting growth factors and cytokines, they can also inhibit inflammatory responses and reduce chondrocyte apoptosis [2].

Cardiovascular System:

MSCs can differentiate into cardiomyocytes and vascular endothelial cells, promoting myocardial regeneration and angiogenesis. In heart diseases such as myocardial infarction, MSC transplantation can reduce infarct size, improve cardiac function, and lower the incidence of heart failure.

For peripheral vascular diseases like arteriosclerosis obliterans, MSCs can promote collateral circulation and alleviate limb ischemia symptoms.

Organ Transplantation:

In organ transplantation, MSCs can induce immune tolerance and reduce the incidence of graftrejection reactions. They can modulate the recipient's immune system, promoting the survival and functional recovery of donor organs.

MSCs can also promote angiogenesis and tissue repair in the transplanted organ by secreting growth factors and cytokines [3].

2. Immune Modulation

MSCs possess immunomodulatory mechanisms acting on both innate and adaptive immunity. They exert their effects through celltocell contact and by secreting bioactive factors such as growth factors, cytokines, and chemokines.

Autoimmune Diseases:

MSCs can suppress overactive immune systems and regulate immune cell function. In autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis, MSCs can reduce inflammation and alleviate disease symptoms.

Nervous System:

In neurological injuries such as stroke and spinal cord injury, MSCs can secrete neurotrophic factors, promoting neuronal survival and regeneration. They also modulate immune responses, reduce inflammatory damage, and promote functional recovery.

For neurodegenerative diseases like Parkinson's and Alzheimer's, MSCs may improve neuronal metabolism and function through the secretion of various bioactive substances, thereby slowing disease progression [4].

3. Anti-Apoptosis

Apoptosis is a hallmark of aging, indicating that cells have lost their capacity for further division and regeneration and are becoming a burden to the body. Stem cells possess anti-apoptotic properties: they not only act as "seed cells" to replenish aged or dead cells but also, through paracrine effects, secrete growth factors (e.g., VEGF, EGF, FGF) and anti-apoptotic factors (e.g., VEGF165, FGF-2, HGF) to prevent mature functional cells from prematurely and excessively entering the aging program.

Skin Anti-Aging:

MSCs can secrete collagen, elastin, and hyaluronic acid, increasing skin elasticity and moisture content while reducing wrinkles and pigmentation.

They also promote the proliferation and differentiation of skin cells, improve skin metabolism, and delay the aging process.

Organ Function Improvement:

With aging, organ functions gradually decline. MSCs can improve the organ microenvironment by secreting growth factors and cytokines, promote cell regeneration and repair, and enhance organ function. In organs such as the liver, kidneys, and lungs, MSCs can reduce tissue damage and improve function.

On September 13, 2024, Chinese researchers published a review in Signal Transduction and Targeted Therapy titled "Pharmacokinetic characteristics of mesenchymal stem cells in translational challenges," which reported clinical research progress on MSCs [5]. As of December 2023, a search on ClinicalTrials.gov with the keyword "mesenchymal stem cells" returned more than 1,600 related clinical trials, of which over 1,500 used MSCs as therapeutic interventions. Overall, MSCs are well tolerated, with most trials reporting no adverse effects in the interim; only a few trials indicated mild and transient reactions during injection.

Current immune and inflammatory disease indications in MSC therapy clinical trials.

Many completed clinical trials have demonstrated the efficacy of MSC infusion in treating various diseases, including graft-versus-host disease (GvHD), multiple sclerosis (MS), Crohn's disease (CD), amyotrophic lateral sclerosis (ALS), myocardial infarction (MI), diabetes mellitus (DM), and acute respiratory distress syndrome (ARDS) [6]. Among these trials, neurological diseases (17%) and joint diseases (15%) were the most common registered indications, followed by cardiovascular diseases (8.8%) and GvHD (8.3%), with a higher proportion in phase III trials. 84% of MSC clinical trials explicitly specified the route of administration.

Clinical Cases of MSC Therapy in Neurological Diseases

1. Paralysis

West China Hospital of Sichuan University Case: The hospital treated a middle-aged man with complete paralysis from a high-altitude fall during paragliding using umbilical cord-derived MSCs. This was part of a clinical research project on stem cell therapy for spinal cord injury. The planned regimen involved four injections, one month apart. In earlier studies at the Third Affiliated Hospital of Sun Yat-sen University, significant results were observed: a paraplegic patient who had been wheelchair-bound for a long time was able to stand after three MSC injections.

2. Stroke

A study published in Frontiers in Medicine reported on five stroke patients aged 46-70 who received umbilical cord-derived MSCs. Each patient received 1-2 × 10⁶ cells. After treatment, patients with limb weakness or immobility due to stroke showed significant improvement in quality of life. One 46-year-old male, treated 7 months post-stroke, began to improve in right-hand weakness after 4 weeks, with significant improvement after 3 months. A 60-year-old female, treated in the second week post-stroke, regained her swallowing reflex, left-hand grip, and experienced marked improvement in left-leg claudication and leftfacial function at 12 months [7].

3. Parkinson's Disease

Bayer AG and its cell therapy subsidiary conducted a Phase I clinical trial of a potential first-in-class cell therapy for Parkinson's disease. The investigational drug, Bemdaneprocel (BRT-DA01), showed good tolerability with no major safety events, demonstrated engraftment feasibility, and provided evidence of cell survival and engraftment at one year.

4. Alzheimer's Disease

Researchers at Samsung Medical Center in Seoul enrolled nine patients with mild-to-moderate Alzheimer's dementia. Three received low-dose (10 million cells/2 mL) and six received high-dose (30 million cells/2 mL) umbilical cord-derived MSCs via three injections (every 4 weeks). Over a follow-up of up to 36 months, no serious adverse events occurred, indicating that the treatment is feasible, safe, and well-tolerated [8].

The application prospects of mesenchymal stem cells are vast. Scientists are conducting extensive research and clinical trials to explore their potential in treating more diseases. While MSC therapy still faces challenges such as safety, efficacy, and standardization, with continuous technological advancement, we have reason to believe that future breakthroughs will be made in treating various diseases with MSCs.

References:

[1] Kimura K, Breitbach M, Schildberg FA, Hesse M, Fleischmann BK. Bone marrow CD73+ mesenchymal stem cells display increased stemness in vitro and promote fracture healing in vivo. Bone Rep. 2021 Sep 29;15:101133.

[2] Li ZQ, Yang JM, Gao F, et al. Mechanisms and application advances of mesenchymal stem cells in promoting cartilage repair for osteoarthritis. Shandong Medical Journal, 2023;63(22):86-90. [in Chinese]

[3] Qiu YC, Zhou XY, Liu F, et al. Progress in the application of mesenchymal stem cells and their exosomes in transplantation. Journal of Tissue Engineering and Reconstructive Surgery, 2023;19(02):184-188. [in Chinese]

[4] Xu Y, Xiao JH. Research progress of mesenchymal stem cells in treating aging-related diseases. Chinese Journal of Gerontology, 2023;43(13):3310-3314. [in Chinese]

[5] Shan Y, Zhang M, Tao E, Wang J, Wei N, Lu Y, Liu Q, Hao K, Zhou F, Wang G. Pharmacokinetic characteristics of mesenchymal stem cells in translational challenges. Signal Transduct Target Ther. 2024 Sep 13;9(1):242.

[6] Wang LT, Liu KJ, Sytwu HK, Yen ML, Yen BL. Advances in mesenchymal stem cell therapy for immune and inflammatory diseases: Use of cell-free products and human pluripotent stem cellderived mesenchymal stem cells. Stem Cells Transl Med. 2021 Sep;10(9):12881303.

[7] Ercelen N, Karasu N, Kahyaoglu B, Cerezci O, Akduman RC, Ercelen D, Erturk G, Gulay G, Alpaydin N, Boyraz G, Monteleone B, Kural Z, Silek H, Temur S, Bingol CA. Clinical experience: Outcomes of mesenchymal stem cell transplantation in five stroke patients. Front Med (Lausanne). 2023 Jan 19;10:1051831.

[8] Kim HJ, Cho KR, Jang H, Lee NK, Jung YH, Kim JP, Lee JI, Chang JW, Park S, Kim ST, Moon SW, Seo SW, Choi SJ, Na DL. Intracerebroventricular injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer's disease dementia: a phase I clinical trial. Alzheimers Res Ther. 2021 Sep14;13(1):154.