Mesenchymal Stem Cell Treatment: Current State and Clinical Updates
Regulatory Status and Clinical Reality
No MSC therapies have received FDA clearance for any clinical indication in humans, despite decades of promising preclinical research. 1, 2 The American Academy of Orthopaedic Surgeons emphasizes that the term "stem cell" has been overused to encompass uncharacterized, minimally manipulated cell preparations, and practitioners must clearly communicate the untested nature of these treatments to patients. 1, 2
What MSCs Actually Are
MSCs are multipotent progenitor cells that can differentiate into osteoblasts, chondrocytes, adipocytes, and myocytes. 1, 3 They are defined by the International Society for Cellular Therapy as plastic-adherent, culture-expanded cells that express specific surface markers (CD73, CD90, CD105) while lacking hematopoietic markers. 1, 3 MSCs can be harvested from bone marrow, adipose tissue, umbilical cord blood, placenta, amniotic fluid, peripheral blood, and olfactory mucosa. 1
Therapeutic Mechanisms
MSCs exert effects primarily through paracrine signaling rather than direct cell replacement. 1 They promote tissue repair through:
- Immunomodulation and suppression of pro-inflammatory cytokines (IL-1β, TNFα, IFNγ) 1, 3
- Secretion of neurotrophic factors and growth factors 1
- Pro-angiogenic signaling to support blood vessel formation 3
- Mitigation of apoptosis and enhancement of cell survival 1
Current Clinical Trial Landscape
Neurological Disorders
For spinal cord injury, multiple Phase I/II trials are ongoing with varying delivery methods:
- Intrathecal delivery: Pharmicell's Phase II/III trial (NCT01676441) uses 3.2 × 10⁷ intrathecal MSCs plus 1.6 × 10⁷ intraparenchymal MSCs for chronic cervical injuries, with results expected in 2020. 1, 4
- CSF administration: Mayo Clinic's CELLTOP study (NCT03308565) delivers 1 × 10⁸ autologous adipose-derived MSCs via lumbar puncture for AIS grade A/B/C injuries, with results expected in 2023. 1, 4
- Umbilical cord-derived MSCs are being tested in multiple Phase I/II trials (NCT03521323, NCT03505034, NCT02481440) for both subacute and chronic injuries. 1, 4
For Huntington's disease, a 2023 meta-analysis of 15 preclinical studies (346 rodent subjects) demonstrated that MSC transplantation increased striatal volume and prevented motor deficits when administered before symptom onset, with bone marrow-derived MSCs showing superior efficacy. 1 However, cognitive improvements were largely absent. 1 Cellavita's NestaCell product (human immature dental pulp stem cells) has completed early clinical trials in Brazil (NCT02728115, NCT03252535) and is now in expanded Phase II/III testing (NCT04219241). 1
Cardiovascular Disease
For ischemic heart disease, the European Society of Cardiology Working Group emphasizes that MSCs represent "first-generation" cell therapy candidates with limited regenerative potential but easier clinical preparation. 1 The major limitation is poor cell retention—while 10-15% short-term engraftment can be achieved, long-term retention (>1 month) drops below 1%, regardless of delivery method (intramyocardial injection, intracoronary perfusion, or retrograde venous delivery). 1 Tissue engineering approaches using biomaterial scaffolds have achieved >80% long-term retention rates. 1
Musculoskeletal Conditions
For osteoarthritis and orthopedic applications, international models provide instructive examples:
- Japan's provisional approval pathway grants conditional authorization for biologics showing safety in small samples with potential therapeutic effect, withdrawing products if efficacy is not demonstrated during postmarket surveillance. 1
- Chile's public-private partnership using culture-expanded bone marrow MSCs has demonstrated low adverse event incidence and suggested efficacy, particularly for OA. 1
The American Academy of Orthopaedic Surgeons recommends that MIBO checklists for cell therapy guide clinical study design, with primary goals of determining efficacy for pain, function, and structure. 1
Critical Safety Considerations
Hemocompatibility is the most serious safety concern. 3 Specific precautions include:
- Single injection doses should not exceed 4 × 10⁶ cells/kg body weight to avoid thrombosis risk. 2
- Frozen-thawed cells should be avoided due to increased adverse events. 2
- Blood compatibility testing must be performed before treatment, particularly for intravascular delivery. 2, 3
- Low-dose anticoagulants like heparin may be necessary when using high-dose cells to control immune-mediated blood reactions. 2
- Tissue factor (TF/CD142) expression varies by tissue source, with adipose and perinatal-derived MSCs showing higher thrombogenic potential than bone marrow-derived MSCs. 3
Source-Specific Differences
MSCs from different tissue sources are not equivalent and cannot be assumed to have the same safety or efficacy profiles. 3 Bone marrow-derived MSCs were the original and most studied source until 2008, but adipose tissue-derived and perinatal tissue-derived MSCs now account for approximately 50% of clinical trials. 3 The concentration of stem/progenitor cells varies dramatically—only 1 in 1,000 to 1 in 1,000 cells harvested from healthy tissues are true stem or progenitor cells capable of differentiation. 1
Emerging Cell-Free Alternatives
MSC-derived exosomes represent a promising cell-free therapeutic approach that mediates cardioprotective, anti-inflammatory, and regenerative effects. 3 Advantages include no risk of cell engraftment issues and potentially easier standardization and scale production. 3 MSC-derived exosomes have been successfully used to treat steroid-refractory graft-versus-host disease. 3 However, limitations include rapid clearance, lack of standardized isolation methods, and uncertainty about optimal dosing. 3
Common Pitfalls to Avoid
Do not offer MSC therapy outside of approved clinical trials. 2 No standardized protocols exist, and FDA approval is lacking for all indications. 1, 2 The substantial heterogeneity in cell preparations, processing techniques, and delivery methods makes it impossible to generalize efficacy or safety data across different MSC products. 1
Do not allow patients to abandon proven therapies for experimental MSC treatments. 2 For metabolic disorders, lifestyle interventions with personalized medical nutrition therapy and physical activity remain the cornerstone of treatment. 2 For cardiovascular disease, established medical and interventional therapies should not be delayed or replaced. 1
Clearly communicate to patients that minimally manipulated cell products are untested and uncharacterized. 1, 2 The consensus recommendation from the American Academy of Orthopaedic Surgeons is that these treatments should be referred to as "cell therapy" rather than "stem cell therapy," and their experimental nature must be explicitly stated. 1
Accelerated Approval Pathways
The 21st Century Cures Act provides potential pathways to accelerate clinical evaluation of autogenous cell sources and culture-expanded cell-based therapies. 1 Patient demand and clinical need, along with international experience showing low adverse event incidence, support exploration of these pathways for musculoskeletal conditions. 1 However, the clinical history with minimally manipulated autogenous cell products suggests these should be considered "lower risk" only when used without genetic modifications. 1