Mesenchymal Stem Cells & the Blood-Brain Barrier (BBB)
Modern studies suggest that Mesenchymal stem cells (MSCs) when administered intravenously, can cross the blood-brain barrier (BBB) leading to various regenerative effects.
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Do mesenchymal stem cells administered via IV cross the blood-brain barrier (BBB)?
Mesenchymal stem cells (MSCs) intrinsically possess unique features that help them migrate towards areas of inflammation. MSCs secrete various types of secretomes to induce nerve regeneration and pain-relieving effects at inflammatory sites. Modern studies suggest that Mesenchymal stem cells (MSCs) when administered intravenously, can cross the blood-brain barrier (BBB) leading to various regenerative effects. This was confirmed by a recent study conducted by Kim et al. which found that MSCs administered intravenously crossed the BBB and migrated into the brain in a mouse model for Alzheimer's Disease. (3)
What is the blood-brain barrier?
The blood-brain barrier (BBB) is a dispersion barrier, which prevents the entry of most compounds from the blood to the brain. According to Ballabh, the barrier is highly particular, meaning it only allows certain substances to cross from the bloodstream into the brain. This protects the brain from toxins that can potentially damage neurons.
Stem cells cross the blood-brain barrier in an animal stroke model
Mesenchymal stem cells represent a great potential to reverse neuronal damage associated with CNS diseases such as Multiple Sclerosis, Parkinson's disease (PD), and Alzheimer's disease (AD). (4)
A study conducted by Yilmaz et al. found that intravenously (IV) injected mesenchymal stem cells (MSCs) can travel through the blood-brain barrier to the cerebral artery occlusion (t-MCAO) model for stroke. (5) The brain tropism (movement into the brain) of MSCs was confirmed by whole-body imaging of radiolabeled (visible radioactive compound) MSCs given to rats. During the first two hours after stroke, MSCs transiently pass through the lungs and continued to migrate over time within the region of brain ischemia, crossing the blood-brain barrier. The study concluded through the use of whole-body imaging that mesenchymal stem cells (MSCs), when administered intravenously were able to populate the CNS after passing through the BBB. (5)
What makes mesenchymal stem cells (MSCs) so special?
Mesenchymal stem cells (MSCs) are an especially attractive therapeutic agent due to their ease of isolation, established safety, and potential to target multiple pathways involved in neuronal regeneration.
MSCs are widely used in the treatment of various diseases due to their self-renewable, differentiation, anti-inflammatory, and immunomodulatory properties. In-vitro (performed in a laboratory setting) and in-vivo (taking place in a living organism) studies have supported the understanding mechanisms, safety, and efficacy of MSC therapy in clinical applications. (6)
Do mesenchymal stem cells get trapped in the lungs?
Studies suggest that pulmonary trapping of stem cells following intravenous administration is only a transient phenomenon, meaning the cells eventually pass through reaching other areas of the body (11). Physical size plays an important role in the migratory capabilities of any cell throughout the body. (see figure below). The size of cells can result in entrapment in certain areas resulting in a loss of migratory abilities. Mesenchymal stem cells (MSCs) can range in size depending on their original source (bone marrow, adipose tissue, cord blood or umbilical cord tissue). Importantly, endogenous MSCs are smaller in size (∼10 μm), which enable efficient trafficking via systemic circulation (10). According to a 2009 study conducted by Majore et al. the average diameter of a single cord tissue-derived mesenchymal stem cell is roughly 11 μm (similar in size to a white blood cell) (9). Mesenchymal stem cells also undergo a process called cellular deformability, which can facilitate passage of larger cells through smaller vessels (10). This data suggests that MSCs can bypass the pulmonary ‘first-pass effect’ (becoming trapped in the lungs) leading to efficient circulation throughout the entire body, including the CNS.
Homing mechanisms of mesenchymal stem cells (MSCs)
One of the key benefits of mesenchymal stem cells is their ability to target specific areas of concern due to their intrinsic homing capabilities. Mesenchymal stem cell homing, when administered systemically can be defined as exiting circulation and migrating to the injury site. (7)
Studies suggest that MSCs may possess leukocyte-like, active homing mechanisms that enable them to interact with and migrate across the BBB under injury or inflammation. (1)
Stem cells administered intravenously can cross the blood-brain barrier
In general, neurological diseases are difficult to treat, partly due to the challenge of getting drugs across the blood-brain barrier (BBB). However, mesenchymal stem cells when administered via IV can cross the blood-brain barrier (BBB). Studies have shown that mesenchymal stem cells rapidly migrate to damaged regions of the brain. This has been confirmed through the use of magnetic resonance-based tracking of the transplanted cells. (1).
The opening into the brain (BBB) is believed to be able to allow for the efficient crossing of MSCs and/or their secretome to the desired site in the brain which results in various regenerative effects such as nerve regeneration, reduction in inflammation, and reduction in pain.
We have found multiple studies that focus on neurological conditions such as Multiple Sclerosis, Parkinson's, Stroke, and ALS which have observed positive outcomes via intravenous injection of mesenchymal stem cells. (8) So, it can be determined that mesenchymal stem cells can cross the blood-brain barrier (BBB) in multiple different disease models. (4, 3, 5)
(1) Liu, L., Eckert, M. A., Riazifar, H., Kang, D.-K., Agalliu, D., & Zhao, W. (2013). From blood to the brain: can systemically transplanted mesenchymal stem cells cross the blood-brain barrier? Stem cells international. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753739/.
(2) Conaty P;Sherman LS;Naaldijk Y;Ulrich H;Stolzing A;Rameshwar P; (n.d.). Methods of Mesenchymal Stem Cell Homing to the Blood-Brain Barrier. Methods in molecular biology (Clifton, N.J.). https://pubmed.ncbi.nlm.nih.gov/30196403/.
(3) Kim, S., Chang, K.-A., Kim, J. a, Park, H.-G., Ra, J. C., Kim, H.-S., & Suh, Y.-H. (2012). The preventive and therapeutic effects of intravenous human adipose-derived stem cells in Alzheimer's disease mice. PloS one. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3458942/.
(4) Trounson, A. (2009, June 11). New perspectives in human stem cell therapeutic research. BMC medicine. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2702289/.
(5) Yilmaz, G., Vital, S., Yilmaz, C. E., Stokes, K. Y., Alexander, J. S., & Granger, D. N. (2011, March). Selectin-mediated recruitment of bone marrow stromal cells in the postischemic cerebral microvasculature. Stroke. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3042505/.
(6) Cona, L. A. (n.d.). Types of Mesenchymal Stem Cells (MSCs) and their Mechanisms of Action. RSS. https://www.dvcstem.com/post/mscs.
(7) Torres Crigna, A., Daniele, C., Gamez, C., Medina Balbuena, S., Pastene, D. O., Nardozi, D., … Bieback, K. (2018, June 15). Stem/Stromal Cells for Treatment of Kidney Injuries With Focus on Preclinical Models. Frontiers in medicine. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013716/.
(8) Petrou, P., Kassis, I., Levin, N., Paul, F., Backner, Y., Benoliel, T., . . . Karussis, D. (2020, November 30). Beneficial effects of autologous mesenchymal stem cell transplantation in active progressive multiple sclerosis. Retrieved February 23, 2021, from https://academic.oup.com/brain/article/143/12/3574/6012789?login=true
(9) Majore, I., Moretti, P., Hass, R., & Kasper, C. (2009, March 20). Identification of subpopulations in mesenchymal stem cell-like cultures from human umbilical cord. Cell communication and signaling : CCS. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2676292/.
(10) Krueger, T. E. G., Thorek, D. L. J., Denmeade, S. R., Isaacs, J. T., & Brennen, W. N. (2018, August 1). Concise Review: Mesenchymal Stem Cell‐Based Drug Delivery: The Good, the Bad, the Ugly, and the Promise. Stem Cells Translational Medicine (AlphaMed Press). https://stemcellsjournals.onlinelibrary.wiley.com/doi/full/10.1002/sctm.18-0024.
(11) Fischer, U. M., Harting, M. T., Jimenez, F., Monzon-Posadas, W. O., Xue, H., Savitz, S. I., Laine, G. A., & Cox, C. S. (2009, June). Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem cells and development. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3190292/.