Scientific Evidence for Stem Cell Therapy in Medicine, Aesthetics, and Anti-Aging
Overview of Scientific Evidence for Stem Cell Therapy
Stem cell therapy is anticipated for regenerative medicine applications in treating various diseases as well as aesthetic and anti-aging purposes. However, the quality of evidence (scientific basis) for its efficacy and safety varies by field, requiring careful evaluation. This article organizes the efficacy, risks, and evidence levels for stem cell exosome infusion therapy, autologous adipose-derived mesenchymal stem cell treatment for cerebrovascular disease, and medical, aesthetic, and anti-aging treatments using adipose stem cells, based on the latest papers and literature. It also compares guidelines and regulations between Japan and overseas, providing a comprehensive evaluation.
Efficacy and Safety of Stem Cell Exosome Infusion Therapy
Overview of Exosome Therapy: Stem cell exosomes are tiny extracellular vesicles secreted by stem cells (particularly mesenchymal stem cells: MSCs), containing proteins and RNA with the ability to influence other cells. Instead of transplanting cells themselves, this therapy aims to achieve stem cell effects while reducing rejection and thrombosis risks by intravenous administration of exosomes.
Evidence on Efficacy: Exosome therapy is being researched globally across numerous disease areas, with 77 clinical trials registered as of 2021. Of these, 11 have been completed, with reports of exosome treatment showing diagnostic and therapeutic effects in cancer, neurodegenerative diseases, blood disorders, and others. For example, research using MSC-derived exosomes for immunomodulation and tissue regeneration shows promising results for intractable diseases. However, in the aesthetic and anti-aging fields (skin aging, pigmentation, alopecia, etc.), no clinical trials of exosomes have been reported yet. Most evidence of effects currently comes from preclinical research (cell cultures and animal experiments) or small clinical studies—for example, results showing promotion of wound healing and anti-inflammatory and anti-aging effects, but large-scale comparative human trials are still to come. Overall, the evidence level for exosome infusion efficacy is currently low to moderate (mainly based on Phase I/II early clinical results), and further verification is needed to confirm effects.
Evidence on Safety: Because stem cell exosomes don't use cells, they're considered to have low risk of immune rejection or cell embolism. Indeed, initial clinical trials reported almost no serious adverse events. For example, umbilical cord-derived MSC exosome local administration for refractory anal fistulas showed fistula improvement in 4 of 5 cases with no side effects reported. Similarly, placenta-derived MSC exosome therapy (11 cases) for non-Crohn's disease complex fistulas showed no safety issues and promising clinical outcomes. Additionally, exosomes have been shown to potentially cross the blood-brain barrier, being researched as an administration route for central nervous system diseases. From the above, the short-term safety of exosome infusion is generally considered good. However, challenges remain including viral/bacterial contamination management during manufacturing and optimization of dosage and frequency, and long-term safety (such as cancer development risk) requires future follow-up.
Evidence Level Evaluation: At the current stage, exosome infusion therapy is evaluated at approximately Evidence Level III (preliminary clinical research stage). While promising results are reported in small intervention studies, there are almost no placebo-controlled randomized controlled trials (RCTs), and evidence accumulation is needed to confirm efficacy for each indication.
Evidence for Autologous Adipose-Derived Mesenchymal Stem Cells for Cerebrovascular Disease Treatment
Treatment Overview: Autologous adipose-derived mesenchymal stem cells (AD-MSCs) are stem cells harvested and cultured from the patient's own adipose tissue, expected to have neuroprotective and regenerative effects through neural cell differentiation induction and secretion of various growth factors. Clinical studies are progressing on intravenous infusion or brain transplantation of these cells for cerebrovascular disease (mainly ischemic stroke).
Evidence on Efficacy: At the preclinical stage, numerous reports show AD-MSCs improve motor and neurological function in animal stroke models, strongly suggesting efficacy (promising in animals, but human verification is challenging). In clinical research, Phase I trials primarily aimed at safety confirmation have been reported. For example, Tsung-Lang Chiu et al.'s 2022 study transplanted autologous adipose-derived stem cells stereotactically into the brains of 3 chronic stroke patients, resulting in improved motor function and activities of daily living with no apparent adverse events. Additionally, in pilot trials with small numbers in Japan and Spain, AD-MSCs were intravenously administered within 2 weeks post-stroke and followed up. One of these, the AMASCIS trial (Phase IIa, Spain), compared AD-MSC IV administration to placebo in patients over 60 with moderate-to-severe stroke. 24-month follow-up results showed AD-MSC administration was safe with no serious side effects or tumor formation (details below), and improvement trends in neurological function scores (NIHSS) were seen in the treatment group. However, with small sample sizes, statistical significance wasn't achieved, and conclusions on efficacy couldn't be drawn. While these small-scale trials show some positive findings, results from large-scale RCTs aren't yet available. Results from ongoing international trials (e.g., acute stroke AD-MSC administration trials planned in Japan) are awaited.
Evidence on Safety: Because autologous adipose stem cells are used, immunological rejection risk is low, and the safety profile is relatively good. In the clinical studies mentioned above, no serious adverse events were reported in most cases. Particularly for acute stroke patients receiving IV administration, no tumor development was confirmed over 2-year follow-up. For brain transplantation in chronic patients, no complications like infection or bleeding were reported, demonstrating safe procedures. However, intravenously administered cells may temporarily accumulate in the lungs (the "lung filter" phenomenon), and theoretical risks like embolism risk with excessive cell numbers or mutation accumulation during culture aren't zero. While current data shows no major safety concerns, careful observation is needed given limited case numbers.
Evidence Level Evaluation: Evidence level for autologous adipose-derived MSC therapy for cerebrovascular disease is currently around IIb (exploratory clinical trial stage). Though placebo-controlled trials have been conducted in small numbers and safety is being confirmed, efficacy has only "showed improvement trends in safety-focused trials," with moderate evidence quality. Depending on results from ongoing large-scale RCTs, evidence level may be elevated.
Efficacy and Risks of Adipose Stem Cell Treatments (Medicine, Aesthetics, Anti-Aging)
Adipose-derived stem cells (ADSCs) are being applied across wide fields including orthopedics, autoimmune diseases, and aesthetics/anti-aging. Below is an overview of main evidence for efficacy (benefits) and risks in each field.
Medical Field Efficacy: In the medical field, there are already approved cases demonstrating efficacy. A representative example is treatment for Crohn's disease-associated perianal fistulas, using local injection of adipose-derived stem cells to promote fistula closure. The ADMIRE-CD trial (Phase III RCT) conducted in Europe injected allogeneic AD-MSC product (darvadstrocel) in refractory complex anal fistula patients, with 1-year fistula remission rates of approximately 50% in the treatment group vs. approximately 34% in the placebo group, significantly higher in the treatment group. Based on these efficacy and safety results, the stem cell product received European drug approval in 2018 and is being used clinically. On the other hand, for other diseases (e.g., myocardial infarction, joint diseases, liver cirrhosis), ADSC treatments are mostly at the clinical research stage. While some trials report symptom improvement and tissue repair marker improvement, there's little evidence showing clear superiority over standard treatment. Therefore, looking at the medical field overall, except for Crohn's disease fistula treatment, the evidence level for adipose stem cell therapy is generally low to moderate (mostly single-center non-blinded trials and case series).
Aesthetic Field Efficacy: In the aesthetic field, there are reports of using adipose-derived stem cells and their culture supernatant (conditioned media) for skin rejuvenation and hair growth. For example, for androgenetic alopecia (AGA), small randomized controlled trials of ADSC culture supernatant local injection or topical application to the scalp showed significant hair growth effects. A half-head comparison trial with 22 subjects showed significantly increased hair count on the treatment side, concluding "very high efficacy was confirmed". Also, for skin anti-aging, reports of intradermal injection of ADSC-derived exosome or growth factor-containing preparations show increased collagen production, improved skin thickness, and reduced wrinkles and pigmentation. Some studies show skin thickness increase and appearance improvement, and overall aesthetic improvement effects are expected. However, many of these are preliminary studies without control groups or case reports, and high-quality trials verifying effects with objective evaluation metrics are lacking. Evidence level is low, and larger placebo-controlled trials are needed.
Systemic Administration for Anti-Aging Purposes: Clinics exist that provide IV stem cell infusions for aging inhibition or systemic rejuvenation purposes, but scientific evidence demonstrating anti-aging effects in humans has not been established. While some animal studies suggest rejuvenation effects, no human studies have proven lifespan extension or improvement in aging markers. Therefore, "stem cell IV for anti-aging purposes" is currently effect unknown and evidence-free (Level V: expert opinion or hypothesis stage). Rather, businesses providing groundless treatments at high prices are being criticized, and regulatory authorities and academic societies in various countries are raising warnings, as described later.
Risks and Safety Issues: Adipose stem cells are basically derived from autologous tissue and considered highly safe, but serious risks can materialize depending on administration site or method. A typical example is a case of erroneous administration to eye disease patients reported in 2017. At a private clinic in the US, autologous adipose-derived stem cells were injected intravitreally into both eyes of age-related macular degeneration patients, and 3 patients suffered bilateral blindness as irreversible side effects. Vision that was 0.4-0.1 before administration dropped to light perception or below after treatment due to retinal detachment and vitreous hemorrhage. This case was reported in the medical journal NEJM and shocked the world as a serious harm example from stem cell therapy misuse. Additionally, risks of infection and tumorigenesis aren't zero either. Cases of bacterial/viral infection from poor management during culture and immune reactions from allogeneic stem cell administration have been reported. However, in properly managed clinical trials, serious infections or tumor formation haven't been reported so far, and safety appears ensured. What's important is that providing treatments without established evidence outside regulations is itself a risk, with the possibility that patients receive potentially dangerous procedures of unknown efficacy.
Evidence Level Evaluation: In the medical field, evidence level differs by disease. Treatment for Crohn's disease fistulas is Level I (efficacy confirmed in multiple RCTs), but for other indications, it's generally Level II-III (early clinical research stage). For the aesthetic/anti-aging fields, while there are promising results, scientific verification is insufficient at Level III or below. Systemic administration for anti-aging purposes is Level V (no evidence). Therefore, while evidence levels for adipose stem cell treatment overall range widely, evidence is lacking in many application areas—a point requiring attention.
Trends from Major Recent Research
Recent major academic journals (Nature, NEJM, The Lancet, etc.) report promising results as well as challenges and concerns about stem cell therapy. Below is a summary of trends by topic.
Regenerative Medicine Success Stories: The Lancet introduced the success of adipose stem cell therapy for Crohn's disease-derived fistulas mentioned above and its approval as a regenerative medicine product. Also, Nature and other journals featured the potential of stem cell-derived exosomes, with early clinical trial results published particularly for COVID-19 pneumonia MSC exosome applications and neurological disease applications.
Cases with Limited Effects: NEJM, Stroke, and other journals have also published clinical trial results for stem cell treatment of stroke. While safety was confirmed, some trials showed no difference from placebo in primary endpoints. For example, chronic stroke patient trials with bone marrow-derived stem cell transplantation (SanBio's SB623 cells) showed significant improvement in some motor function indicators but failed to achieve statistical significance in overall functional recovery, concluding further verification is needed. Thus, dramatic improvement as expected wasn't demonstrated in some reported cases, showing the reality that stem cell therapy isn't a panacea.
Warnings about Risks and Ethics: NEJM reports (the blindness cases mentioned above) and JAMA reviews have pointed out harms and ethical issues caused by unapproved stem cell treatments. Particularly in the US, unapproved treatment clinics have proliferated, and serious complications (blindness, infection, spinal cord injury worsening, etc.) have occurred in some patients, with FDA officials and experts advocating the need for strengthened regulation and patient education.
Technology Development and Outlook: Meanwhile, technology development to improve stem cell therapy quality is also advancing. Latest literature introduces mass production methods for exosomes, research on genetically modified MSCs to enhance specific therapeutic effects, and exploration of more effective administration routes (e.g., intranasal administration to reach the brain). Nature-series journals increasingly feature discussions on "how to bring stem cell therapy to practical stages" such as optimizing stem cell dosage and timing, and conferring target-directiveness to exosomes. Overall, the tone in major journals is "transitioning from initial hopeful observation to scientific verification and optimization stages." That is, there's recognition that we've entered a phase of determining truly effective indications and methods while considering limitations and failure cases as well as promising ones.
Comparison of Guidelines and Regulations in Japan and Overseas
Japan's Regulations (Act on the Safety of Regenerative Medicine, etc.): In Japan, the "Act on the Safety of Regenerative Medicine" (ASRM) was enacted in 2014, introducing a system for notification and review of regenerative medicine provision plans. Under this law, regenerative medicine is classified into Type 1 (high risk) to Type 3 (low risk) based on risk, with mandatory submission of plans to the Ministry of Health, Labour and Welfare after review by specialized committees. Characteristically, for autologous cell therapy (medium to low risk) using the patient's own cells, clinical provision is possible without drug approval. That is, with certain procedures, clinics can provide stem cell treatments and collect fees from patients. On the other hand, confirmation of efficacy is not a mandatory requirement, so the system design allows cases of commercial provision with insufficient scientific basis. Indeed, after ASRM implementation, 3,467 regenerative medicine provision plans have been notified in Japan, reportedly including "treatments that could be criticized internationally as evidence-insufficient." Experts point out issues of "lack of scientific verification" and "blurred boundary between treatment and research," with concerns that patients may suffer harm unable to distinguish between unapproved treatments and established medicine. Meanwhile, Japan also has the regenerative medicine product approval system based on the PMD Act (Pharmaceuticals and Medical Devices Act), through which products showing certain efficacy and safety in trials have been commercialized via conditional early approval systems (e.g., conditional approval of iPS-derived cell sheets for heart failure). In short, Japan's system has two tracks: (1) drug approval route and (2) medical practice provision route, with the latter having lower provision hurdles than other countries, but evidence assurance remains a challenge.
Overseas (US, Europe, etc.) Regulations: In the US, most stem cell treatments fall under FDA (Food and Drug Administration) jurisdiction as "drugs" or "biologics." Even with patient's own cells, if there's processing beyond minimum manipulation (enzyme treatment, culture expansion, etc.) or use for purposes different from original body function (non-homologous use), FDA's new drug approval process must be followed. Therefore, adipose-derived stem cell IV infusions and exosome product administration basically require verification and approval through clinical trials, and provision for commercial purposes before approval is prohibited. Recently, FDA has strengthened crackdowns on illegal stem cell clinics, with warning letters and injunctions (permanent injunctions) enforced against businesses advertising stem cell treatments. For example, businesses selling unauthorized umbilical cord blood-derived products causing serious infection cases have been warned by FDA and had products recalled. FDA also officially urges patients to "confirm whether stem cell treatments are FDA-approved or under trial protocols when receiving them." In Europe, stem cell treatments are also strictly regulated under the European Medicines Agency (EMA), with stem cell products classified as Advanced Therapy Medicinal Products (ATMPs). While EMA is cautious about approving stem cell products, those demonstrating efficacy like darvadstrocel are being approved. In Europe, conversely, there's basically no loophole to provide unapproved stem cell treatments as medical practice like in Japan, with ongoing debate balancing criticism of "limiting patient treatment opportunities" against safety measures of "protecting patients."
Guidelines and Academic Society Views: The International Society for Stem Cell Research (ISSCR) and medical societies in various countries have issued ethical guidelines on providing stem cell treatments. ISSCR guidelines state that stem cell treatments without sufficient scientific basis should not be clinically provided, and patients should be enrolled in clinical trials to build evidence. Japan's Society for Regenerative Medicine also states that "even under regenerative medicine provision plans, informed consent should be thorough, and risks and uncertainties should be fully explained." In the aesthetic field, there have been instances where the Japan Society of Aesthetic Plastic Surgery issued statements cautioning about "aesthetic procedures claiming to use stem cells." Regarding regulation, exosome products have no FDA-approved examples in the US yet, and regulatory authorities view even cosmetically-sold products as problematic. In Japan too, treatments using exosomes may fall under Type 3 regenerative medicine, requiring notification.
As seen above, there are significant differences between Japan and overseas in stem cell treatment provision systems and regulations. Japan has a flexible system emphasizing early provision to patients, but risks treatments with unestablished evidence being performed; overseas (especially US and EU) have a cautious system prioritizing safety and efficacy confirmation, but patients may take longer to access approved treatments. Each has advantages and disadvantages, but ultimately appropriate evidence-based operation is required to maximize patient benefit.
Conclusion: Comprehensive Evaluation and Future Outlook
Stem cell therapy holds great potential as a pillar of regenerative medicine, but evidence levels vary by field and indication. In the medical field, some applications have confirmed effects in RCTs (e.g., adipose-derived MSC for refractory fistula treatment), but in many disease areas, they're at early clinical research stage with limited efficacy backing. In the aesthetic/anti-aging field too, while promising reports on hair growth and skin regeneration exist, placebo-controlled trials are lacking and scientific proof hasn't been achieved. Meanwhile, safety is relatively good as long as autologous cells are used, but serious adverse event risks from improper indications or management failures have actually been reported. Regarding regulations, while Japan has review processes, provision with lax evidence requirements is possible, whereas overseas maintains approval-based, evidence-focused stances.
Comprehensively, stem cell therapy is currently established as standard medicine in only limited areas, with most being in the "promising but insufficient evidence" stage. From an evidence level perspective, many applications must be evaluated as Level 3 (preliminary research) or below. Therefore, when providing to patients, it's important to fully explain current evidence and uncertainties without confusing research and treatment. Additionally, it's expected that through further accumulation of high-quality clinical trials, stem cell therapy evidence levels will be elevated, and safe and effective new medical and aesthetic applications will be realized.
References: Cited from latest academic papers and reviews including exosome therapy literature, stroke clinical trials, NEJM blindness case reports, Japanese regulatory system analysis in Cell Stem Cell, and ADMIRE-CD trial results.