Wharton's Jelly cells are stem cells derived from Wharton's Jelly, a substance found within the umbilical cord and collected at the time of delivery. Wharton's Jelly is a soft connective tissue that encases the blood vessels within the umbilical cord, and this region is a rich source of mesenchymal stem cells (MSCs).
Specifically, Wharton's Jelly-derived mesenchymal stem cells (WJ-MSCs) are noted for their reduced immunogenicity upon allogeneic transplantation and are considered highly promising in next-generation stem cell therapies.
In this article, we explain the scientific reasons why WJ-MSC are not easily rejected, by addressing their complex immunological background, thereby allowing you to receive stem cell therapy in Malaysia with peace of mind.
What is Rejection? Its relationship with HLA.
In medical transplantation, "rejection" refers to the process by which the immune system identifies a transplanted organ or cells as foreign (non-self) and subsequently mounts an immune response to attack and eliminate them.
Our immune system is normally responsible for protecting the body from pathogens such as viruses and bacteria; however, in transplant therapy, this defensive function paradoxically creates complications.
For instance, in organ transplantation, when immune cells recognize surface markers on the transplanted organ as "foreign," lymphocytes and other cells initiate an attack, leading to damage to the transplanted organ. This phenomenon is known as "rejection."
The protein HLA (Human Leukocyte Antigen) is critically involved in this immune identification process. HLA molecules are present on the surface of virtually all cells and serve as a unique cellular identification marker for each individual. Immune cells scrutinize these HLA molecules to determine whether a cell is "self" or "non-self."
Therefore, in transplantation, an HLA mismatch between the donor and recipient typically leads the immune system to recognize the transplanted cells as foreign, thereby increasing the likelihood of rejection.
To prevent such rejection, medical institutions typically conduct meticulous compatibility testing to maximize the match between donor and recipient HLA types. Furthermore, should a risk of rejection persist, immunosuppressive medications can be administered as needed to suppress immune function and facilitate a safe transplantation.
Why are Wharton's Jelly cells so compelling?
WJ-MSCs exhibit several immunological characteristics that contribute to their reduced immunogenicity. Key features include:
Very Low HLA Antigen Expression
A characteristic of WJ-MSCs is their low expression of Human Leukocyte Antigen (HLA) on the cell surface. HLA is a crucial marker utilized by immune cells to distinguish "self" from "non-self," and in transplantation therapy, it is a key molecule in immune rejection.
Specifically, MHC class I antigens (HLA-ABC) are expressed at very low levels, and MHC class II antigens (HLA-DR), which are highly reactive to another individual's immune system, are virtually unexpressed.
Due to this low expression, WJ-MSCs are not readily recognized by immune cells, especially T cells, as foreign bodies.
Consequently, the immunogenic properties of WJ-MSCs—their ability to elicit an immune response—are significantly suppressed, and a high acceptance rate can be anticipated even for allogeneic transplantation (cells from another individual).
Lacks co-stimulatory signals that activate immune cells.
Typically, for the immune system to mount a strong response to external foreign substances, two signals are required. The first signal is the recognition of "HLA antigens," and the second signal is an additional stimulus referred to as "co-stimulatory signals."
Lymphocytes, such as T cells and B cells, require both signals for full activation and to initiate an attack.
Co-stimulatory signals are mediated by molecules such as CD80 and CD86; however, studies have shown that Wharton's Jelly stem cells (WJ-MSCs) minimally express these co-stimulatory molecules.
Therefore, even if WJ-MSCs are recognized by immune cells, the "attack command" from the second signal is not transmitted. This prevents full T cell activation and consequently does not readily induce rejection.
This feature is a primary factor enabling WJ-MSC to be well-tolerated within the body.
Secreting immunosuppressive cytokines to suppress inflammation.
Wharton's Jelly stem cells (WJ-MSCs) are not only immunoprivileged but also possess a regulatory function that modulates local immune system activity.
Its primary function is cytokine secretion, which are intercellular communication substances.
WJ-MSCs are known to secrete high levels of anti-inflammatory cytokines, such as Interleukin 10 (IL-10) and Transforming Growth Factor β (TGF-β), which suppress excessive immune responses.
These substances inhibit excessive immune cell activity and modulate inflammatory responses, thereby creating an environment less conducive to immune responses.
In this manner, WJ-MSCs establish a local microenvironment that suppresses immune responses. Consequently, transplanted cells demonstrate enhanced stability in vivo and readily engraft. This mechanism is a critical factor in preventing graft rejection.
Expressing HLA-G, a Molecule Involved in Immune Tolerance
Wharton's Jelly stem cell (WJ-MSC) is known to express a specific HLA molecule called "HLA-G". HLA-G is an "immune tolerance factor" that functions to prevent fetal rejection by the maternal immune system during pregnancy, and is also found naturally.
By expressing HLA-G, WJ-MSCs, when transplanted into the body, are less prone to immune rejection. HLA-G is known to promote the expansion of regulatory T cells (Tregs), which suppress immune function, and has been shown to mitigate exaggerated immune responses.
In this way, WJ-MSCs not only possess a structure that is not readily recognized as antagonistic by the immune system, but also have the capacity to actively modulate immune responses and foster a tolerogenic environment within the body.
POIN:As explained above, Wharton's Jelly stem cells have three balanced characteristics: "unobtrusive", "non-stimulating", and "actually calming the immune system". This combination results in a very low risk of rejection even though the cells come from another person, which is one of their unique characteristics.
Wharton's Jelly does not contain blood.
A primary reason for the reduced likelihood of rejection observed with Wharton's Jelly stem cells (WJ-MSCs) is the absence of blood components within Wharton's Jelly tissue.
This is highly relevant to immunological safety during allogeneic WJ-MSC transplantation.
Wharton's Jelly, located in the umbilical cord, is a connective tissue that encases blood vessels. Due to its location, this tissue does not contain red or white blood cells. Therefore, when stem cells harvested from this region are transplanted, the likelihood of donor blood group antigen admixture or donor immune cells (lymphocytes) is very low.
This means that the risk of donor blood components being introduced into the body intact can be prevented, which constitutes a significant technical and immunological advantage.
Even when stem cells harvested from other tissues, such as bone marrow, are transplanted, it has been confirmed that ABO blood group antigens are minimally expressed. Consequently, stem cell transplantation can be successful even without blood group compatibility.
However, as WJ-MSC is characterized by the absence of blood-derived components from the initial collection stage, it serves as a reassuring additive.
Furthermore, due to Wharton's Jelly cell products being less likely to be contaminated with donor immune cells such as T cells and B cells, the risk of "graft-versus-host disease (GVHD)," where the graft attacks the recipient's immune system, is also very low.
Thus, the avascular structure is a facilitating factor in preventing immune rejection for WJ-MSC, and is of significant importance.
Comparison of Rejection Risk: Wharton's Jelly, Bone Marrow, and Adipose-Derived Stem Cells
Preventing immune rejection of transplanted cells is a critical concern in stem cell therapy. Here, we compare three types of stem cells: Wharton's Jelly-derived stem cells, bone marrow-derived stem cells, and adipose-derived stem cells (assuming autotransplantation).
Wharton's Jelly Mesenchymal Stem Cell (WJ-MSC)
- WJ-MSC exhibit minimal expression of HLA antigens, particularly showing negligible expression of HLA-DR, which is known to readily react with immune cells.
- Furthermore, it lacks T-cell co-stimulatory molecules (e.g., CD80, CD86) and possesses a structure resistant to immune cell attack.
- Secreting high levels of immunosuppressive cytokines such as IL-10 and TGF-β, creating an environment where inflammation is suppressed and immune function remains quiescent.
- The cells are derived from newborn umbilical cord tissue, are exceptionally young, and remain unaffected by environmental damage or aging.
- The harvested Wharton's Jelly tissue is devoid of blood components, which significantly minimizes the risk of ABO blood group antigen or donor immune cell admixture, thereby ensuring a high safety profile.
- Based on these characteristics, WJ-MSCs are anticipated to exhibit excellent transplantation compatibility, even for allogeneic transplantation.
Bone Marrow-Derived Stem Cell (BM-MSC)
- Bone marrow-derived MSCs express HLA class I (HLA-ABC) at a moderate level, and HLA-DR (class II) expression is readily inducible in the body's inflammatory environment, rendering them susceptible to immune targeting.
- In certain situations, it can express co-stimulatory molecules, which can activate T cells and trigger rejection responses.
- Despite the secretion of IL-10 and TGF-β, their inhibitory effects demonstrated reduced suppressive potency compared to WJ-MSC and varied with the individual's age.
- Bone marrow collection involves invasiveness, and with cells derived from older donors, concerns exist regarding increased immunogenicity and functional decline.
- Given this background, BM-MSCs are relatively safe for autotransplantation; however, allogeneic transplantation may necessitate immunosuppressive measures.
Adipose-Derived Stem Cell (AD-MSC, assuming autologous transplantation)
- In autotransplantation using autologous adipose-derived stem cells, the immune system does not identify the transplanted material as non-self, theoretically eliminating the risk of rejection.
- Given identical HLA types, the risk of immune rejection is very low, and preliminary compatibility testing is not required.
- However, it cannot be entirely excluded that unforeseen reactions might occur, depending on the local immunological environment, when transplanted into an inflammatory site.
- Additionally, cells obtained from donor adipose tissue are influenced by the donor's age and health status, and both cell quality and regenerative capacity can vary considerably among individuals.
- While the immunological safety of autologous transplantation against rejection is robust, challenges persist concerning cell function and the stability of its effects.
In stem cell therapy, immunological safety considerations regarding rejection are paramount. The following is a comparative summary of the three types of stem cells.
Summary
The reduced likelihood of rejection for Wharton's Jelly-derived mesenchymal stem cells (WJ-MSCs) stems from several immunological characteristics. Firstly, their very low expression of Human Leukocyte Antigen (HLA) makes them difficult for immune cells to detect, lending them an "immunologically quiescent" nature. Secondly, they possess almost no co-stimulatory molecules that activate T-cells, thereby maintaining a "non-immunogenic" state for the immune system. Furthermore, by secreting immunosuppressive cytokines such as IL-10 and TGF-β, and by expressing HLA-G, which is involved in immune tolerance, WJ-MSCs have the ability to actively promote immune acceptance. The combination of these elements allows allogeneic WJ-MSCs to be well-tolerated *in vivo* and readily engraft after transplantation. The intrinsic "immune tolerance" characteristic of WJ-MSCs makes them highly distinctive cells from an immunological perspective and a very promising option in stem cell and regenerative therapies. Ongoing research is underway, and in the future, WJ-MSCs are expected to serve as a "universal stem cell source" that can be used without concerns about rejection, leading to broader application in various medical treatments.