Unless we resolve this, it will have a tremendous negative impact on stem-cell research.
Transplantation of fetal cells to repair non-functional neuronal tissue is only one field of cell therapy where we can trace long-term (5-15 years) outcome. That’s because clinical cellular neurotransplantation started to get explored as early as 20 years ago. The rational was quite simple – replace damaged brain tissue by the same functional tissue taken from an aborted fetus.
I’ll try to summarize only some histological findings of individuals who underwent clinical neurotransplantation and eventually died from different reasons. I’d like to focus on fetal graft pathological findings that were discovered many years (7-15) after transplantation. There are a number of reports that indicate short-term morphology and function of fetal neurograft is actually good, which is usually associated with positive clinical outcome. One of the best studies was done on Parkinson’s Disease (PD) patients and published in 2001. Now, let’s look at some interesting published cases.
The first? bizarre case in 1996 – PD patient got transplant in China
We report the case of a 52-year-old man, who, 23 months earlier, received both intrastriatal implantation and intraventricular infusion of tissues derived from fetuses of 15 to 16 weeks and 5 to 6 weeks gestational age. Clinical improvement, as measured by increased amounts of “on” time with reduced levodopa requirements, seemed to occur over the subsequent months. He died suddenly at home after a several-hours interval of progressive lethargy and breathing difficulties.
At autopsy, the diagnosis of PD was confirmed. Intrastriatal graft sites were identified, but contained no viable neurons; astrogliosis, focal microgliosis, and mixed inflammatory response, suggesting allograft rejection, were present. Surprisingly, the intraventricular tissues survived and showed ectodermal and mesenchymal, but no neural, differentiation, as well as cellular response; the left lateral and fourth ventricles were filled completely by this proliferated tissue.
Parkinson’s Disease affected grafts
… three independent laboratories report their autopsy-controlled findings in a total of eight subjects after such surgery.The long-term clinical benefits in six individuals who survived 9–16 years after surgery proved to be limited, and three of them showed brain pathology typical of Parkinson’s disease at autopsy—alpha-synuclein inclusions (Lewy pathology).
…The findings—such as the development of parkinsonian pathology in some transplanted neurons—underscore the limitations of this approach.
Huntington’s Disease (HD) – graft degeneration in 10 years
Two of 3 patients with HD reported here, who underwent neural transplantation containing striatal anlagen in the striatum a decade earlier, have demonstrated marginal and transient clinical benefits.
Here we report in patients with HD that (i) graft survival is attenuated long-term; (ii) grafts undergo disease-like neuronal degeneration with a preferential loss of projection neurons in comparison to interneurons; (iii) immunologically unrelated cells degenerate more rapidly than the patient’s neurons, particularly the projection neuron subtype…
To remind you about this scandalous clinical case I refer you to my earlier post – Potential risk of tumor formation from adult stem cell therapy could be underestimated.
A boy with ataxia telangiectasia (AT) was treated with intracerebellar and intrathecal injection of human fetal neural stem cells. Four years after the first treatment he was diagnosed with a multifocal brain tumor. The biopsied tumor was diagnosed as a glioneuronal neoplasm.
Why was it a scandal? Because news media have taught that “stem cell therapy caused tumor formation”. Sounds like a horrible impeachment of the whole cell therapy field. Ridiculous! But a few days ago I was so happy to see an independent investigation of this case by the experts:
Our review of their data, together with unpublished studies performed contemporaneously on similar material from the same Moscow institution, argue that the report is inaccurate: the cells implanted were not NSCs (Neural Stem Cells).
Furthermore, the histopathologic picture of the cellular accumulation is not one of neoplasia. Neoplasia, too, has a rigorous definition with archetypal features that were unfulfilled by the photomicrographs shown in the study.
Taken together, the findings from the two cases suggest that an unselected, unfractionated
whole fetal forebrain homogenate, not an NSC infusion, was administered—in inappropriate doses, in inappropriate locations, by an inappropriate route and for inappropriate cell replacement indications. In both instances, an unfortunate neurologic condition was worsened, and the suffering of the children was exacerbated.
Some lessons to learn
1. Fetal neural tissue transplantation for replacement of affected non-functional host brain probably have only short-term clinical effect in some conditions (PD, HD) in some patients and linked to graft survival.
2. Long-term outcome and morphological findings raises a question about future of this therapeutic approach. It’s like a long-playing pill – give some symptoms release in some patients for 1-3, maybe 5 years and then… But would you get a new pill like that in your brain?
3. All of these transplant cases (or most of them) were done not under government regulation and didn’t use “defined cell product”. This is a difference from modern trials, so we can’t extrapolate.
4. None of these cases described that “stem cells” were injected. Seem like none of them describe tumor formation, but some unclear cell proliferation (Chinese and Moscow’s cases).
5. Wrong interpretation of these findings by mass media and absence of independent expertise could lead to unfortunate cell therapy field discredit.
picture credit: GEOFF TOMPKINSON / SCIENCE PHOTO LIBRARY