What is mesenchymal infusion?

What is Mesenchymal Infusion?

Mesenchymal infusion refers to the intravascular (intravenous or intra-arterial) delivery of multipotent mesenchymal stromal/stem cells (MSCs) as a therapeutic intervention, currently being investigated in hundreds of clinical trials for various conditions including autoimmune diseases, tissue injury, and inflammatory disorders. 1

Cell Sources and Product Types

MSCs can be derived from multiple tissue sources, each with distinct characteristics:

• Bone marrow-derived MSCs (BM-MSCs): The original and most extensively studied MSC source, historically preferred due to their role in supporting hematopoiesis 1
• Adipose tissue-derived MSCs (AT-MSCs): Increasingly popular but demonstrate the highest procoagulant activity 2
• Perinatal tissue-derived MSCs (PT-MSCs): Including umbilical cord-derived cells, showing intermediate procoagulant properties 2

These different tissue sources now account for approximately 50% of MSC products in clinical trials, representing a major diversification from the original BM-MSC-only approach. 1

Mechanism and Therapeutic Rationale

MSCs exert their therapeutic effects through:

• Immunomodulatory properties: Suppressing excessive immune responses and modulating inflammation 3, 4
• Secretion of growth factors: Promoting tissue healing and regeneration 3
• Paracrine signaling: Rather than long-term engraftment, as studies show minimal MSC persistence in recipient tissues 1

Critical Safety Considerations

Instant Blood-Mediated Inflammatory Reaction (IBMIR)

The most significant safety concern with mesenchymal infusion is triggering IBMIR, which can lead to thrombosis, embolization, and potentially fatal complications. 1

• Tissue factor (TF) expression on MSC surfaces is the primary determinant of blood incompatibility, activating the coagulation cascade 2
• AT-MSCs exhibit the strongest procoagulant activity and have been associated with lethal effects in preclinical models and cases of pulmonary embolism in patients 1, 5
• BM-MSCs trigger weaker IBMIR responses, contributing to their established safety profile 1
• PT-MSCs (umbilical cord) have caused venous thrombosis in patient forearms, requiring thrombolytic therapy 1

Dose-Dependent Risks

• AT-MSCs at doses of 4×10⁶ cells/kg body weight cause significant increases in clotting parameters and fibrinolytic responses 2
• Higher doses of any MSC type increase thrombotic risk 1

Anticoagulation Requirements

The American College of Cardiology and International Society for Stem Cell Research strongly recommend routine use of low-dose anticoagulants (such as heparin) when administering high-dose MSCs. 2

• Anticoagulation prevents coagulation-related adverse events and may improve cell efficacy 2
• Many early clinical trials included patients already receiving antiplatelet drugs, low molecular weight heparin, or dextran sulfate, which may have masked safety issues 1

Current Safety Profile

• Meta-analysis confirms that first-generation BM-MSC infusion is safe with minimal serious adverse events 1, 3
• A comprehensive literature review of thousands of infusions identified only two serious adverse events (upper extremity thromboembolisms in patients with preexisting renal disease) 3
• However, safety data cannot be extrapolated from BM-MSCs to AT-MSCs or PT-MSCs due to vastly different TF expression profiles 1

Clinical Application Standards

All cellular therapies intended for intravascular delivery should undergo hemocompatibility screening before clinical application, according to ISO 10993-1/4 standards. 2

Key quality control factors affecting IBMIR include:

• Cell culture expansion degree 2
• Culture medium composition 2
• Cryopreservation and thawing processes (frozen MSCs may cause more adverse events than fresh cells) 6
• Washing methods and cell suspension buffers 2

Contraindications

• Severe blood system diseases: Increased thrombosis risk per European Society of Cardiology 2
• Severe cardiopulmonary impairment: Risk of microembolism worsening function per American Thoracic Society 2
• Pregnancy, HIV coinfection, or hepatitis B/C infection 4

Current Clinical Stance

The American College of Rheumatology/Arthritis Foundation strongly opposes stem cell injection therapy for osteoarthritis due to lack of standardized preparation methods, technical specifications, and product heterogeneity making it impossible to determine what is actually being injected. 6