[BBB/Stem Cells] Do stem cells cross the blood-brain barrier? A quick overview of the literature

This post is related to a recent testimony of Rhonda, a follower of my Facebook page, that asked me whether stem cells can cross the BBB. As a BBB and stem cell scientist, this was a very good question asked. If I have to tell my thought in a sentence, I would it’s complicated. To support my claim, I will use the recent review from Aylenik and colleagues (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106911/) and Liu and colleagues (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753739/)

First, it is important to remember the reader about what is a stem cell and what are the different types of stem cells. A stem cell is a particular type of undifferentiated cells capable of self-renewal and capable to differentiate into any cell type following the right molecular and environmental triggers.
In the scientific research, we have different types of human stem cells: we have firstly the pluripotent stem cells coming from embryos (human embryonic stem cells or hESCs) or from reprogrammed adult cells (induced pluripotent stem cells or iPSCs). These are the most used in basic research because they have the most potency to differentiate into any cell type. However these are also the type of stem cells that have the most important concerns in terms of safety as such undifferentiated cells rapidly develop aggressive tumors.
The second type of stem cells that are more in use in clinical research are stem cells derived from placental cord blood or from bone marrow (hematopoietic stem cells or HSCs) or from the stroll fraction of adipose tissue (mesenchymal stem cells or MSCs). These cells have a much less pluripotency as these cells are already engaged into a defined lineage. However this lineage restriction make these cells much less prone for developing tumors and are considered safe.

Now let’s get into the details. In this post, we will not talk about stem cell delivery that bypass the BBB such as intranasal, intrathecal or intracerebroventricular injections. We are discussing here about intra-arterial or intra-veinous injection of stem cells and their delivery across the BBB, in particular the delivery of MSCs across the BBB.

One interesting aspect of the MSCs delivery is their particular attraction to sites of injury, including inflammation sites as mentioned in Liu’s review. What we know is that MSCs can cross in vitro models of the BBB (cell culture models) but yet we have a very limited number of studies that have demonstrated similar approaches  in animal models.
The mechanism by which such MSCs may cross the BBB appears to use similar keys used by leukocytes to infiltrate across the BBB but also may include a localized degradation of the basement membrane (a biological mesh lining blood vessels) to allow their infiltration. However, as mentioned by Liu in his review, early clinical trials have shown mixed if not negative results (see Ankrum J et al., Trends in Molecular Medicine 2009; Karp et al., Cell Stem Cells 2009).

Stem cell-based therapies have a important potential to improve regeneration following injury, but yet claims that such stem cells can cross the BBB remains weak and still needed to be demonstrated. Yet, a recent trend observed in the US and in other countries is the emergence of “stem cell clinics” and the subsequent “stem cell tourism”. Such clinics that operates on protocols not approved by the Food & Drug Administration and not published in peer-reviewed journals (to ensure their efficacy and reproducibility) often laud “miraculous claims”, promising patients to cure their diabetes, knee arthritis if not more serious neurological disorders including stroke, Alzheimer’s disease, autism spectrum disorders, lysosomal storage disorders, cerebral palsy or multiple sclerosis.

The main problem with these clinics is not only their claims are not based on science-based medicine, but also until now stem cell therapies in academic settings (including university hospitals) are still in their infancies (Phase I and IIA clinical trials), mostly focusing on the safety of such therapy before we can consider assessing their efficacy.

Such “therapies” are indeed very costly ($30’000+ price tags) but also the nature of such treatment remains shoddy and unclear. Worse, a recent case report recently published by the New England Journal of Medicine (http://www.nejm.org/doi/full/10.1056/NEJMc1600188) reported the case of the growth of a proliferative lesion on the spinal cord of a patient that underwent such “stem cell therapy” following a stroke injury. Indeed, a recent opinion letters written by Turner and Knoepfler in Cell Stem Cell discuss more deeply more about such recent phenomenon (http://www.cell.com/cell-stem-cell/fulltext/S1934-5909(16)30157-6).

In conclusion, stem cell therapies have shown interesting potentials in pre-clinical models and early stages of stem cell therapies are providing optimistic news about the use of certain stem cells to assess their clinical efficacy in a rigorous and reproducible experimental paradigm, especially for aiming to treat neurological diseases.
However, the delivery of such cells remains an important challenge with a weak literature to support the claim that such cells can cross the BBB once injected via IV route.

In addition, because stem cells have an important potential, a recent rise in stem cell clinics promoting unproven treatments raises questions of safety and concern for vulnerable patients to what appears to me as a rise of a new generation of “snake-oil sellers”.








8 thoughts on “[BBB/Stem Cells] Do stem cells cross the blood-brain barrier? A quick overview of the literature

  1. I had a question regarding the clinics you are referring to in relation to Clinical trials being conducted at duke university. I have read quite a bit and i notice their protocols are essentially the same. However duke is currently only using autologous cord blood cell while a clinic in panama for example is using mesynchymal stem cells from donated cord blood. both places are injecting intravenously. do you have any thoughts on these procedures?
    furthermore do you have any idea which cells would be more neurogenic in nature msc from cord blood or autologous stem cells derived from adipose tissue?


    • Hi s.d.m thanks for your comment.
      First, the pluripotency of MSCs from adipose tissue and cord blood to become neurons remains to be evaluated side-by-side. As their name mentions, these cells have a mesenchymal origin, deriving from the primitive mesoderm. In the other hand, neurons have a neurectoderm origin, such neurectoderm derives from ectoderm. I doubt that MSCs maybe differentiate as-is into neural cells with little manipulation, however there are reports of differentiation protocols capable to produce neural progenitors cells straight from somatic cells without passing through the iPSC reprogramming stage (https://www.ncbi.nlm.nih.gov/pubmed/28648365).
      Second, there is a fog building over clinical trials, with for-profits stem cell clinics posing as clinical trial centers. Let me be clear and sincere about this: there is not yet any stem cell therapy approved by the FDA with the exception of bone-marrow stem cell transplantation for patients with leukemia. Therefore, stem cell clinics making claims of curing all sort of conditions are deceptive, acting as “snake-oil sellers”. Now, there is a registry at clinicaltrials.gov that list clinical trials ranging from Phase I to Phase III. Some unscrupulous stem cell clinics use this portal as a cover to sell their “treatment”, claiming that they are applying “the right to try” but also charging their patients for that right. This can have severe consequence on the patients health (see the story of patients that lost their vision and some of their wealth in Florida due to “clinical trials” done by some stem cell clinics).
      Clinical trials are NEVER charging patients for the cost. Patients may receive a renumeration but this is only under certain conditions and ALWAYS accompanied by a letter of consent from the institution research board (IRB).
      If you decide to follow the path of clinical trial for stem cells, there are my advises:
      1. Clinicaltrials.gov is not a tacit FDA approval. It is just a directory listing all clinical trials submitted without any oversight. You should navigate them very closely.
      2. Check the affiliation. Reputable stem cell clinical trials ALWAYS occurs in University-affiliated hospitals, usually high-ranking institutions like Duke University or Harvard.
      3. Check the PI affiliation and publication record. Is the PI cited in the Clinicaltrials.gov effectively affiliated with the University he/she claims or did he/she just hold a degree from that University? Check the faculty roster. Also check his/her publication record in Pubmed. Did he/she published into the field (example he/she propose a stem cell trial for MS, does he/she has publication records in MS in peer-reviewed journals).
      Hope that helps 🙂


    • In theory yes, we can hypothesize that the mannitol opening maybe large enough to allow cells to extravasate. But there is a lot of unknown on this: how big are the tight junction pore size following mannitol induction, can stem cells squish into that pore size…..So far, I would assume the main entrance (based on what we know with immune cells) is the need of cell surface anchors to allow cells to cross the blood-brain barrier.


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