Written by: Sun Yat-sen University, Light Blue
Review expert of this article: Professor Li Jing from the Affiliated Hospital of Jiangsu University
introduction
In recent years, mesenchymal stem cells have been widely used in different populations, and in a large number of clinical data, we can see that there are significant individual differences in the effect of mesenchymal stem cell therapy, which is not only related to the patient's health status and disease state, but also may be affected by factors such as the route of administration, dose, preparation method, and cell quality of mesenchymal stem cells. This article analyzes 10 literatures and explains why the effects of mesenchymal stem cells are different for different people from three dimensions: treatment regimen, preparation of mesenchymal stem cells, and quality of mesenchymal stem cells.
Mesenchymal stem cells (MSCs), with their self-renewal ability and multi-directional differentiation potential, have become a hot research focus in the field of regenerative medicine. Not only are these stem cells capable of transforming into a diverse range of cell types, but they also exhibit powerful immunomodulatory properties [1], opening up new avenues for the treatment of a range of diseases and providing new clinical treatment options.
Image from Ref. 1)
MSCs have been widely used in therapeutic research in different populations due to their low immunogenicity and strong immunomodulatory ability, which can largely overcome the limitations of major histocompatibility barriers and achieve a relatively unhindered transplantation process [2].
However, in clinical practice, the efficacy of stem cell therapy for various diseases shows significant differences among patients, which may not only be related to the patient's health status and disease state, but also may be affected by factors such as the route of administration, dose, preparation method, and cell quality of MSCs. This article analyzes the literature and takes you to understand why the effect of mesenchymal stem cells is different for different people from three dimensions: treatment plan, preparation of mesenchymal stem cells, and quality of mesenchymal stem cells.
Impact of treatment regimens:
Indications, routes of administration, dosages, etc., will all lead to differences in effectiveness
In clinical practice, different treatment regimens, such as different indications, drug selection, frequency of treatment, length of treatment, etc., may produce different results. Similarly, the outcome of stem cell therapy will be closely related to factors such as how the stem cells are administered, the dose of administration, and the indication targeted.
According to the literature [9], stem cell administration methods can be broadly divided into three categories:
There are three common types of stem cell administration
The first type is systemic administration - intravenous or arterial administration, which is more used in the treatment of neurasthenia, Alzheimer's disease, systemic lupus erythematosus and other systemic diseases;
The second type is the widely used local area delivery drugs - subcutaneous injection, intramuscular injection and intrathecal injection, etc., which are commonly used in orthopedics, obstetrics and gynecology, gastrointestinal system and other related diseases;
The third type is the attachment of stem cells to biomaterials for drug delivery using bioscaffolds/bioengineered constructs, which is often seen in the field of regenerative medicine.
Different administration methods of stem cells, such as intravenous injection and local injection (such as intra-articular injection, intraspinal cord injection, etc.), will lead to significant differences in treatment effects due to their different pathways and distribution into the body.
Studies have shown [3] that compared with systemic drugs, injection of MSCs into the lesion area of the body in the form of targeted local injection can effectively increase the paracrine activity of MSCs and enable them to secrete protective paracrine factors, thereby prolonging/enhancing the therapeutic potential of stem cell therapy.
In addition, factors such as the choice of injection site, the characteristics of the syringe (e.g., size and shape), the carrier material, and the formulation of the buffer may have an impact on the effectiveness of cell administration.
It can be seen that choosing the appropriate administration method according to different indications can more accurately guide stem cells to reach the lesion, thereby improving the efficacy.
In addition to the route of administration, the injected dose of stem cells also has an impact on efficacy. In clinical practice, the cell dose is related to factors such as the degree of disease, the type of disease, and the mode of administration.
At present, the optimal dose of MSCs in therapeutic applications is not uniform and depends on the type of treatment, but more studies usually use 1.0–2.0 × 10 6 MSCs per kg of body weight as their ideal dose, and Chiho et al. counted the latest 47 clinical studies of MSCs, which are still dominated by 1.0–2.0 × 10 6 MSCs per kg of body weight [4], as shown in the figure below.
(Image from Ref. 3)
From clinical trials, it can be seen that the clinical effect of different doses of mesenchymal stem cells is still the focus of clinical research.
Effects of mesenchymal stem cell preparation:
Results vary depending on the production environment
In addition to the different routes of administration and dosage that will affect the efficacy of stem cell therapy, the different preparation methods of MSCs are also likely to affect the efficacy of treatment. According to literature [4], several clinical trials of mesenchymal stem cells have been completed worldwide, and many more are ongoing, and clinical trials have confirmed the feasibility and safety of this approach. However, the isolation and expansion protocols for mesenchymal stem cells in these trials vary widely, which may affect the efficacy of treatment.
For example, flasks, culture media, and expansion agents for culturing stem cells, as well as the seeding density, passage, and storage conditions of stem cells, are all different. Taking seeding density as an example, cell seeding density is an important factor affecting MSC yield efficiency, as it affects the adhesion of MSCs, contamination of other cell types, and subsequent growth rate of adherent MSCs. These factors also affect the quality of the final mesenchy stem cell preparation and affect the final use effect.
(Image from Ref. 4)
In the future, stem cell therapy may become mainstream in the medical field, but only a few centers are currently able to produce and supply stem cell preparations that meet clinical-grade requirements.
It has also been highlighted in the literature [5] that stem cell products produced under GMP conditions and effectively regulated can effectively improve the therapeutic efficiency of stem cell therapy.
The diagram below summarizes the main steps of MSC manufacturing under the GMP process.
Image from Document 5
Effect of mesenchymal stem cell quality:
age, origin, and heterogeneity
除了上述的两大因素外，近期，发布在“Cells”上面的一篇“Universal or Personalized Mesenchymal Stem Cell Therapies: Impact of Age, Sex, and Biological Source”新综述还阐述了间充质干细胞的质量——包括间充质干细胞供者的年龄、来源、不同性别间充质干细胞的差异，也可以对干细胞疗法疗效产生影响[6]。
(Image from Ref. 6)
(1) The function of mesenchymal stem cells will be different depending on age
When it comes to the efficacy of stem cell therapy, there is no doubt that individual age is one of the most important factors affecting the function of MSCs. The study shows that the proliferation and differentiation ability of MSCs decreases significantly with age, as shown in the figure below. This phenomenon has been validated not only in MSCs cultured in vitro, but also in animal experiments and clinical studies [7].
(Image from Ref. 7)
From the above results, it is not difficult to see that MSCs in the elderly show decreased proliferative ability, reduced differentiation potential, and morphological changes. For example, elderly MSCs are more likely to experience cell aging when cultured in vitro, which is manifested by increased cell volume, morphological changes, and increased β-galactosidase activity. In addition, the ability of elderly MSCs to resist oxidative stress is also significantly reduced, resulting in cells being more susceptible to damage and accelerating aging.
(2) The function of mesenchymal stem cells is also different depending on the gender
In addition to age, gender is another important factor affecting the function of MSCs. Studies have shown that there are significant differences between males and females in terms of immune response and the biology of MSCs. Stefano et al. found that the sex of the donor also had an effect on the proliferation and differentiation ability of MSCs [8], and the main experimental results are shown in the figure below.
(Image from Ref. 8)
From the above results, we can see that the expression of Rankl and Opg genes is higher in osteoblasts from males, which increases the ability of MSCs to differentiate into osteoblasts. In addition, in females, the amount of IL-6 produced by adipose-derived MSCs was higher, suggesting that there were also differences in cytokine secretion between genders.
(3) The effect of mesenchymal stem cells is different depending on the cell source
In addition to age and gender, the source of MSCs can also affect their efficacy. MSCs can be obtained from a variety of tissue sources, including bone marrow, adipose tissue, and umbilical cord/placenta, and MSCs from different sources may vary in biological characteristics and therapeutic efficacy, so selecting the appropriate tissue-derived mesenchymal stem cells for different indications is critical to the final clinical outcome.
Bone marrow-derived mesenchymal stem cells
Bone marrow-derived MSCs are one of the first MSCs to be discovered and widely studied. These cells have strong osteogenic and chondrogenic differentiation capabilities, making them suitable for the treatment of diseases such as osteoarthritis. However, obtaining BM-MSCs requires invasive surgery and causes some pain to the patient.
Adipose-derived mesenchymal stem cells
Mesenchymal stem cells from adipose tissue (ASCs) are isolated from tissue samples obtained after medical interventions involving liposuction or lipectomy. Adipose tissue is obtained by aspiration or excision of adipose tissue or subcutaneous adipose tissue located in the abdomen, humerus, femur, or buttock area, followed by collagenase digestion of adipose tissue, removal of red blood cells by specific erythrocyte lysis, and finally cell filtration.
Adipose stem cells secrete vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), fibroblast growth factor (FGF2), transforming growth factor (TGFβ), etc., which promote angiogenesis and wound healing, and play an important role in tissue wound repair and regeneration. It is widely used in the fields of plastic repair such as fat grafting, skin flap grafting, wound healing, scar repair, hair regrowth and anti-aging.
Umbilical cord/placenta derived mesenchymal stem cells
Umbilical cord-derived MSCs are not limited by donor age and health status, and have strong differentiation ability and immunomodulatory functions. In addition to the more common hematopoietic support functions, umbilical cord-derived mesenchymal stem cells also have osteogenesis, adipogenesis, nerve, cartilage, and myocardial differentiation effects.
It has been found that umbilical cord-derived mesenchymal stem cells have a stronger adipogenic capacity than other derived mesenchymal stem cells. Therefore, it is more advantageous in the field of diseases that require fat cells, such as fat filling, hair loss, and liver failure. It has also been found that the use of umbilical cord stem cells can also be used for arterial reconstruction in ischemic limb disease and vaso-occlusive disease [10].
Cells of placental tissue exhibit greater generation doubling time, proliferative potential, differentiation capacity, and phenotypic stability compared to cells from other tissues. Studies have found that placental mesenchymal stem cells have good osteogenic ability, and are expected to be used as seed cells for bone tissue engineering in congenital bone defects, bone tumors, trauma and other fields.
As of April 2024, hundreds of clinical trials on placental and umbilical cord mesenchymal stem cells have been registered on the ClinicalTrials.gov of the United States Clinical Trial Center, involving indications including idiopathic pulmonary fibrosis, Peyronie's disease, diabetic foot ulcer, type II diabetes, aplastic anemia, obligatory spondylitis, myelodysplastic syndrome, fetal myelomeningocele, impotence, osteoarthritis, COVID-19 pneumonia, graft-versus-host disease, knee osteoarthritis, etc.
brief summary
It can be seen that the effect of mesenchymal stem cell therapy in practical application shows obvious individual differences. This difference is not only closely related to the patient's own health status and the state of the disease, but also related to the route of administration of the cell, the dose, the source of the cell, the function of the cell, whether the preparation process of the cell meets the requirements, whether the quality of the final cell preparation meets the requirements and other factors. Therefore, in clinical practice, we need to be more cautious, accurately grasp each variable, and formulate personalized therapies suitable for patients.
At present, mesenchymal stem cells have been applied to a large number of disease treatment research, and in the future, with the continuous progress of technology and the accumulation of clinical experience, mesenchymal stem cells are expected to become the nemesis of more stubborn diseases and contribute more to the cause of human health.
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