[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”.








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