One common concern about intravenous mesenchymal stromal cell or stem cell therapy is that the cells become trapped in the lungs and therefore cannot provide any benefit.
Many intravenously administered MSCs are initially retained in the small blood vessels of the lungs. This is called the pulmonary first-pass effect. However, this does not automatically mean that IV MSC therapy is useless, nor does it mean that the patient has developed a pulmonary embolism.
Current research suggests that MSCs may act mainly through biological signaling and interactions with the recipient’s immune system, rather than by traveling in large numbers to a distant organ and permanently replacing damaged cells.
Whether these biological effects provide a meaningful clinical benefit must still be evaluated separately for each condition.
What Is the Pulmonary First-Pass Effect?
ACells administered through a vein travel to the right side of the heart and then enter the pulmonary circulation before reaching the rest of the body.
Culture-expanded MSCs are often larger than the narrow capillaries within the lungs. Published research commonly reports MSC diameters of approximately 15 to 30 micrometers, although size varies according to the cell source, culture process, passage, and preparation method. Pulmonary capillaries may measure approximately 5 to 10 micrometers.
This difference in size is one reason many MSCs are temporarily retained in the lungs after IV administration.
Cell size is not the only factor. Cell deformability, surface adhesion molecules, cell aggregation, dose, concentration, infusion speed, and the patient’s health can also influence pulmonary passage.
Do the Cells Remain in the Lungs Permanently?
Not necessarily. Cell-tracking studies suggest that detectable MSCs within the lungs generally decrease over time. Some cellular signals may later be found in the liver, spleen, and other tissues. Many infused MSCs appear to lose viability and are eventually cleared by the recipient’s immune system.
Research in this area has limitations. Some tracking labels remain detectable after a cell has died. A signal found in another organ may therefore represent an intact cell, a cell fragment, or material taken up by an immune cell.
It is more accurate to describe the effect as initial pulmonary retention rather than permanent trapping of every infused cell.
Does Pulmonary Retention Make IV MSCs Useless?
No, but it changes how the proposed mechanism should be explained.
It was once expected that infused MSCs would travel directly to an injured organ, permanently engraft, and become replacement tissue. Current research suggests that this is unlikely to be the main mechanism of most MSC therapies.
MSCs release cytokines, growth factors, extracellular vesicles, and other biological signals that may interact with immune and inflammatory pathways.
Research also suggests that some MSCs undergo programmed cell death after pulmonary retention. Immune cells, including macrophages, then recognize and clear them through a process called efferocytosis. Experimental studies indicate that this interaction may influence the behavior of the recipient’s immune cells.
These findings provide a possible explanation for how IV MSCs may produce biological effects without permanently reaching a distant organ. However, much of the detailed mechanistic evidence comes from laboratory and animal research.
A biological response does not by itself prove that an IV infusion will improve symptoms or change the course of a particular disease.
Is the Pulmonary First-Pass Effect the Same as Pulmonary Embolism?
No. These terms describe different processes. The pulmonary first-pass effect refers to the initial retention of infused cells within the small blood vessels of the lungs.
Pulmonary embolism, or PE, is a blockage of a pulmonary artery, most often caused by a blood clot. Normal pulmonary retention after MSC infusion does not mean the patient has developed a PE. However, factors such as cell aggregation, tissue factor expression, dose, concentration, infusion speed, manufacturing quality, and the patient’s medical history can influence risk.
This is why careful patient screening, quality-controlled cell preparation, appropriate dosing, controlled infusion, and medical monitoring remain important.
What Does Current Safety Evidence Show?
A 2026 systematic review and meta-analysis evaluated intravascular UC-MSC administration across 42 randomized controlled trials involving 2,280 adults.
UC-MSC administration was associated with an increased occurrence of fever. The analysis did not identify a clear signal of harm for the other predefined outcomes, including thrombotic and thromboembolic events. None of the included trials were stopped early because of safety concerns. Hum C, et al. Stem Cells Translational Medicine. 2026.
These findings are reassuring at an overall research level. However, they do not prove that every UC-MSC product, manufacturing process, dose, or clinical protocol has the same safety profile. Safety depends on both the cellular product and the patient receiving it.
When Is Lung Retention a Limitation?
Pulmonary retention is an important limitation when treatment is described as delivering large numbers of intact cells directly to the brain, knee, kidney, heart, or another distant organ.
It is not accurate to say that all MSCs administered through an IV automatically locate damaged tissue and rebuild it.
If a treatment goal requires direct exposure to a specific structure, local administration may sometimes be more anatomically relevant. For example, an intra-articular injection delivers the product directly into a joint.
Targeted delivery also introduces different procedural risks and does not guarantee a better clinical result. The route must be chosen according to the condition, treatment objective, anatomy, evidence, and patient safety.
What May IV MSC Therapy Be Designed to Do?
IV MSC administration is generally investigated for systemic biological effects rather than direct structural replacement.
Possible areas of research include:
- Immune system regulation
- Inflammatory signaling
- Communication between immune cells
- Vascular and tissue-supporting signals
- The biological environment involved in repair
Evidence from one disease cannot automatically be applied to another. Findings involving an inflammatory condition do not prove effectiveness for osteoarthritis, neurological disease, kidney disease, or general anti-aging treatment.
How Should Physicians Select the Delivery Route?
The route of administration should follow the medical objective.
Physicians may consider:
- Whether the intended effect is local or systemic
- The location and severity of the condition
- The evidence supporting that route
- Risks associated with a targeted procedure
- Medical history and relevant imaging
- The characteristics of the cellular product
- Available conventional treatments
For a knee condition, local injection may be more anatomically relevant. For a proposed systemic immunomodulatory effect, IV administration may have a clearer biological rationale.
Neurological conditions require additional consideration because of the blood-brain barrier, procedural risks, and limitations of current evidence.
No delivery route can make a treatment effective if the underlying clinical evidence does not support its use.
Frequently Asked Questions
Do all IV stem cells become trapped in the lungs?
No. Many MSCs are initially retained in the pulmonary circulation, but the proportion varies according to the product, dose, preparation, infusion conditions, and patient factors.
How long do MSCs remain in the lungs?
Detectable cells generally decrease over hours or days. Many cells lose viability and are cleared by immune cells, although the exact timeline varies between studies and products.
Can IV MSCs still reach other organs?
Some cells or cellular material may reach other tissues, but IV infusion does not distribute equal numbers of intact MSCs throughout the body.
Does pulmonary retention mean that I have a blood clot?
No. Pulmonary retention is a biodistribution effect. A pulmonary embolism is usually an artery blockage caused by a blood clot. They are not interchangeable terms.
Does a higher cell dose help more cells pass through the lungs?
Not necessarily. A higher dose does not guarantee better tissue delivery or a better clinical result. Dose should be based on the cellular product, condition, protocol, and patient.
Is IV infusion better than local injection?
Neither route is universally better. IV administration may be considered for systemic biological effects, while local injection may be more appropriate for a specific joint or tissue.
Does lung retention prove that IV MSC therapy works?
No. Pulmonary retention and immune interaction may help explain possible mechanisms, but effectiveness must be demonstrated through condition-specific clinical outcomes.
Does lung retention prove that IV MSC therapy is useless?
No. It suggests that MSCs are unlikely to work mainly by traveling in large numbers to distant organs and replacing damaged cells. Their proposed effects may instead involve biological signaling and immune interaction.
Many intravenously administered MSCs are initially retained in the lungs. This pulmonary first-pass effect limits the number of intact cells that can reach distant organs, but it does not automatically make IV MSC therapy useless or mean that a pulmonary embolism has occurred.
The appropriate question is whether the cellular product, dose, delivery route, and proposed mechanism are medically reasonable for the patient’s specific condition.
About EDNA Wellness
EDNA Wellness is a surgeon-led regenerative medicine center in Bangkok, specializing in orthopedic and neurological conditions using Umbilical Cord-Derived Mesenchymal Stem Cells (UC-MSCs).
All cases are reviewed by orthopedic surgeons and neurosurgeons, with a focus on clinical indication, patient safety, and realistic treatment expectations. Stem cell therapy is recommended selectively, and alternative treatments are considered when more appropriate.
For more information or to book a consultation:
LINE: @ednawellness
WhatsApp: +66 (0) 64 505 5599
www.ednawellness.com
References
- Fischer UM, et al. Pulmonary Passage Is a Major Obstacle for Intravenous Stem Cell Delivery: The Pulmonary First-Pass Effect. Stem Cells Dev. 2009. https://pmc.ncbi.nlm.nih.gov/articles/PMC3190292/
- Quiñones-Vico R, et al. Biodistribution of Mesenchymal Stromal Cells After Administration in Animal Models and Humans: A Systematic Review. J Clin Med. 2021. https://pmc.ncbi.nlm.nih.gov/articles/PMC8268414/
- Pang SHM, et al. Mesenchymal Stromal Cell Apoptosis Is Required for Their Therapeutic Function. Nat Commun. 2021. https://pmc.ncbi.nlm.nih.gov/articles/PMC8586224/
- Thompson M, et al. Cell Therapy With Intravascular Administration of Mesenchymal Stromal Cells Continues to Appear Safe: An Updated Systematic Review and Meta-Analysis. EClinicalMedicine. 2020. https://pmc.ncbi.nlm.nih.gov/articles/PMC6970160/
- Leibacher J, Henschler R. Biodistribution, Migration and Homing of Systemically Applied Mesenchymal Stem or Stromal Cells. Stem Cell Res Ther. 2016. https://pmc.ncbi.nlm.nih.gov/articles/PMC4709937/
- Hum C, et al. Safety of Intravascular Administration of Umbilical-Cord-Derived Mesenchymal Stromal Cells: An Updated Systematic Review and Meta-Analysis. Stem Cells Transl Med. 2026. https://pmc.ncbi.nlm.nih.gov/articles/PMC13237491/