Peripheral Artery Disease (PAD) is a condition in which arteries that carry blood from the heart to the legs narrow or become blocked due to atherosclerosis (plaque buildup), leading to restricted blood flow.
Due to inadequate blood supply to the lower extremities, patients experience symptoms such as calf pain and tingling during ambulation that resolves with rest. In severe cases, this can progress to severe rest pain, poorly healing wounds, or digital ulcers.
Advanced PAD is called Critical Limb Ischemia (CLI), a serious condition which, if left untreated, can lead to gangrene and, in the worst-case scenario, limb amputation.
When arteries narrow due to plaque, blood flow deteriorates, and the muscles and skin in the legs do not receive sufficient oxygen and nutrients, which causes the symptoms of PAD.
For PAD, treatment primarily aims to prevent progression and alleviate symptoms through lifestyle modifications and pharmacological therapy (e.g., blood thinners or vasodilators).
Additionally, when vascular occlusion is severe, catheter-based angioplasty procedures (e.g., percutaneous transluminal angioplasty (PTA) or stent placement) or surgical vascular reconstructive procedures such as bypass are performed.
While many patients show improvement with this treatment, there are numerous cases where atherosclerosis extends diffusely throughout the lower extremities, rendering surgical intervention challenging, or patients are unable to tolerate surgery due to severe complications.
Indeed, approximately 10-30% of patients with severe CLI are categorized as 'no-option' for vascular reconstruction, and effective treatment options are currently limited. In these refractory cases, pain and ulceration often do not resolve, ultimately necessitating partial limb amputation.
Amidst the limitations of current medical treatments, there is a pressing need for the development of novel therapeutic methods for patients desperately seeking to preserve their own limbs.
Peripheral Artery Disease and Stem Cell Therapy: New Possibilities for Regenerative Medicine
Therefore, recent focus has been directed towards a novel approach in regenerative medicine, specifically utilizing stem cell therapy. Stem cell therapy is a medical treatment method that employs stem cells—the foundational cells of our body—to promote the regeneration of damaged tissues.
For limbs with restricted blood flow due to arterial occlusion, the objective is to inject stem cells and endogenously generate new blood vessels to enhance blood flow. Rather than "artificially creating a bypass pathway" through surgical bypass, this approach promotes the formation of natural bypasses (collateral circulation) by leveraging the inherent capabilities of stem cells.
Indeed, for CLI patients lacking conventional treatment options, such a regenerative medicine approach is anticipated as a novel strategy.
There are various types of stem cells, but those primarily used in regenerative medicine for peripheral artery disease are mesenchymal stem cells (MSCs) or mononuclear cells derived from bone marrow and peripheral blood.
Specifically, MSCs can be extracted from various body parts such as bone marrow, adipose tissue, and the umbilical cord. By culturing and expanding them, the required number of cells can be secured, making MSCs a potent cell source for regenerative medicine.
MSCs possess superior capabilities in producing growth factors that regenerate blood vessels and suppress inflammation, and have demonstrated their potential to contribute to the improvement of peripheral artery disease. Among those that have recently garnered attention are umbilical cord-derived stem cells isolated from "Wharton's Jelly," the gelatinous tissue within the umbilical cord (Wharton's Jelly-derived MSCs, WJ-MSCs).
These are stem cells derived from perinatal tissues, including the placenta, offering numerous advantages such as high proliferative and differentiation potential. They eliminate the need for autologous cell extraction, thereby reducing patient burden. Furthermore, they can be cultured and expanded to supply a large number of patients.
Furthermore, it has been reported that WJ-MSCs possess a high capacity for secreting substances involved in angiogenesis and anti-inflammation, and hold great promise as a cell source for regenerative medicine for peripheral artery disease.
Mechanism of Action of Stem Cell Therapy for Peripheral Artery Disease
Stem cell therapy is considered effective for peripheral artery disease, as stem cells operate as "multifunctional therapists" that concurrently fulfill numerous roles. The following mechanisms of action are broadly understood for stem cell therapy.
Promoting the growth of new blood vessels (promotion of angiogenesis)
Stem cells secrete copious amounts of substances, known as growth factors and cytokines, which act as angiogenic signals in damaged tissue. This activates surrounding cells and promotes the sprouting of new capillaries, thereby forming a natural vascular bypass at the cellular level (a process referred to as collateral circulation formation).
For example, bone marrow-derived mononuclear cells, which contain endothelial progenitor cells (EPCs), are also reported to strengthen vascular tissue when incorporated into the walls of new blood vessels as part of the newly formed vasculature.
Anti-inflammatory and immunomodulatory actions.
In regions with compromised blood flow, an inflammatory response develops in addition to the tissue damage caused by vascular occlusion. This inflammation further exacerbates damage to blood vessels and tissues, creating a vicious cycle.
Stem cells also release anti-inflammatory cytokines that mitigate inflammation, thereby exerting a protective effect on an overactive immune system. Consequently, tissue damage from unwarranted inflammation and pain are alleviated, and a healing environment is established.
Tissue protection and repair promotion (cell protection and anti-fibrosis)
Secreted factors from stem cells are not only angiogenic and anti-inflammatory, but also protect tissue cells and suppress fibrosis (scarring).
Administering cytoprotective factors, which promote cell survival, to hypoxic skeletal muscle cells helps prevent tissue necrosis. Furthermore, severe inflammation during periods of oxygen deprivation often leads to fibrosis of the injured tissue. Stem cells possess the capacity to prevent this.
Stem cell therapy involves the injection of cells such as bone marrow-derived mesenchymal stem cells (BM-MSCs), mononuclear cells (BM-MNCs), or endothelial progenitor cells (EPCs) from peripheral blood into areas of the leg with poor blood flow. Initially, these cells secrete bioactive substances like growth factors, cytokines, and enzymes to promote vascular regeneration. Consequently, this facilitates the formation of new capillaries in the surrounding tissues and improves blood flow.
Furthermore, stem cells release substances that mitigate inflammation, suppressing damage resulting from excessive immune responses. Additionally, they also serve to prevent "fibrosis (scarring)," characterized by the stiffening of damaged tissue.
Through these stem cell interventions, cells such as skeletal muscle, damaged by oxygen and nutrient deprivation, are protected, and the structure and function of muscle and skin are more readily maintained.
In this manner, stem cell therapy not only promotes vascularization but also facilitates blood flow restoration, controls inflammation, and provides tissue protection and repair through multiple mechanisms, thereby contributing to the alleviation of symptoms in peripheral artery disease and the promotion of recovery.
Evidence of Effectiveness of Stem Cell Therapy for Peripheral Artery Disease
Stem cell therapy holds theoretical promise, but the crucial question is its actual efficacy.
In fact, over the past approximately 20 years, numerous clinical studies on stem cell therapy in patients with Peripheral Artery Disease (PAD) and Critical Limb Ischemia (CLI) have been conducted worldwide. As a result, positive data demonstrating the effectiveness of stem cell therapy has gradually accumulated.
For instance, in Japan, a trial involving the injection of bone marrow cells into the legs of Critical Limb Ischemia (CLI) patients was conducted in 2002. This study reported the alleviation of leg pain, accelerated ulcer healing, and even a reduction in amputation rates. This research (the TACT trial by Tanabe and Yuasa) garnered international attention and became a precursor to cell therapy for Peripheral Artery Disease (PAD).
Recently, not only small trials but also meta-analyses synthesizing results from numerous clinical trials have been published. One such meta-analysis integrated the analysis of 23 randomized controlled trials targeting CLI patients (a total of 962 individuals), evaluating the efficacy and safety of stem cell therapy (PubMed ID: 29977308).
As a result of the analysis, the group that received stem cells demonstrated the following improvements compared to the group receiving only conventional treatment:
- Recalcitrant leg ulcers are demonstrating improved healing (a positive wound healing trend).
- Indicators of angiogenesis were significantly increased, promoting new capillary formation.
- Increased blood flow and oxygen indicators such as the ankle-brachial index (ABI) and transcutaneous oxygen pressure (TcO₂)
- Reduction of foot pain at rest and increased pain-free walking distance (improved ambulation)
- Reduction in the risk of foot amputation (lower limb amputation) over a specified period.
As a result, patients receiving stem cell therapy demonstrated improvements in objective indicators of blood flow, symptoms, and motor function. Furthermore, a reduction in the proportion of patients requiring major amputation has been shown.
While some research indicates variability in effectiveness levels, it is generally suggested that limbs deemed unsalvageable with conventional treatment could potentially be saved through stem cell therapy.
Furthermore, clinical studies utilizing novel stem cell sources, specifically umbilical cord-derived mesenchymal stem cells (WJ-MSCs), are emerging. For instance, in a Phase I clinical trial reported in 2024, allogeneic WJ-MSCs were injected into the leg muscles of patients with severe critical limb ischemia (CLI) complicated by diabetes, and their safety and efficacy were evaluated.
Consequently, all treated patients remained free from limb amputation (including toe amputation) for six months, and no serious adverse events were reported. Furthermore, at six months post-treatment, significant reductions in foot pain (VAS score), prolonged pain-free ambulation time, and improved foot function scores (FADI) were observed.
Despite the small patient cohort, this is a significant report demonstrating substantial improvement achieved with the latest WJ-MSC therapy, characterized by reduced leg pain and improved ambulation (PubMed ID: 38112806). Furthermore, numerous clinical trials for PAD therapy employing various stem cell types are currently underway in countries worldwide, and new evidence continues to accumulate.
This cumulative research brings stem cell therapy closer to becoming a more established treatment option.
Safety of Stem Cell Therapy for Peripheral Artery Disease and Side Effects
In the context of novel therapies, safety and side effects are also potential concerns.
In summary, current studies have reported overall good safety for stem cell therapy in peripheral artery disease. An integrated analysis of multiple clinical trials identified no serious adverse events (SAEs) associated with stem cell therapy.
Notably, there have been no reports of severe immune rejection reactions or treatment-related deaths, and no significant safety concerns are deemed to exist. Conversely, for CLI patients who lack conventional treatment options, the potential benefits may outweigh the risks.
Indeed, the reported adverse effects were remarkably mild. For instance, transient pain or swelling at the cell injection site, or low-grade fever or fatigue during infusion were occasionally observed; however, all were transient in nature and resolved with appropriate management.
Minor internal bleeding (hematoma) following injection has also been reported; however, these instances resolved spontaneously and were not considered problematic. Essentially, no complications more serious than these have been reported.
Furthermore, regarding the use of allogeneic stem cells, the anticipated rejection reactions have not been observed. This is attributed to the inherent immunomodulatory properties of MSCs, which makes it difficult for the introduced cells to be attacked or rejected.
Regarding safety, stem cell therapy is a minimally invasive therapy administered via injection or infusion. Compared with major surgical interventions, such as extensive bypass procedures in thoracic or peripheral vasculature, the physical burden on patients is substantially mitigated.
Even in the aforementioned clinical trials of umbilical cord-derived stem cells, no adverse effects were reported during the six-month follow-up period. Beyond the inherent safety of the stem cell therapy itself, the patient-friendly nature of the treatment process constitutes a significant advantage.
Based on the foregoing, stem cell therapy for peripheral artery disease emerges as a novel and relatively safe therapeutic option for clinical adoption.
Conclusion
For patients with peripheral artery disease (PAD), stem cell therapy is a regenerative medicine that holds the potential to bring new hope even to severe cases where light is difficult to see.
Although not yet established as a mainstream treatment method, this represents an evolving frontier where active clinical research is being conducted both domestically and internationally, leading to its gradual introduction into the medical field. Furthermore, it is anticipated that its combined use with conventional treatments will manifest synergistic effects, potentially further enhancing treatment outcomes for vascular diseases in the future.
The important thing is not to give up on "there is no more treatment."
With advancements in stem cell therapy, limbs that previously would have necessitated amputation may now be salvaged. This also offers substantial peace of mind for patients and their families.
Patients with peripheral artery disease or those considering stem cell therapy are advised to consult a specialized medical institution or their treating physician. They should expect to receive a comprehensive explanation of the most appropriate options, informed by the latest research advancements.
We hope that this new stem cell therapy will translate into the joy of enhanced mobility and an improved quality of life for you in the future.