Stem cell hype in clinical tissue engineering of hollow organs

by Alexey Bersenev on April 10, 2016 · 1 comment

in tissue engineering

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As you may know, the scandal around “tissue engineering pioneer” Paolo Macchiarini is unfolding and getting uglier (read here and here). To be honest, since 2008 I was really thrilled by initial results of the first trachea transplants and by Macchiarini’s confidence. What I did not like since the beginning was “stem cell branding”. Macchiarini’s technique involves seeding of trachea matrix (synthetic or decellularized) with autologous bone marrow mononuclear cells as well as injection of growth factors into the graft during surgery. I was trying to find any evidence in Macchiarini’s reports for regeneration of tissue engineered trachea by bone marrow (BM)-derived stem cells, but I was not able to. Instead, I’ve learned from Christopher Breuer’s work that exogenously seeded BM stem cell have no (or very little) significant role in regeneration of tissue engineered hollow organ after transplantation:

Breuer said that BM MNC are gone completely from the TEGV as soon as within a week after implantation. But with time TEGV got endotheliazed in situ, in other words – fully functional neovessel was formed. It turns out that BM MNC is not a source of endothelium and smooth muscle cells in neovessel, but only a source of monocyte-macrophages and pro-inflammatory cells (reviewed here). He showed that endothelium and smooth muscle cells are coming to neovessel from edges of anastamosis.

You can learn more about Breuer’s work on blood vessels here and here. Similarly to endotheliazion of engineered blood vessels, epithelial migration from the anastomoses, was recently showed by Breuer in experimental trachea transplantation model. If we look at other models of tissue engineered hollow organs, such as ureter, we can see that BM cells do not differentiate in neotissue:

The mean microvessel density was significantly increased in tissues seeded with BM-MNCs. However, cell-tracking experiments revealed that the increased number of capillaries in the experimental group was not due to the direct differentiation of transplanted endothelial progenitor cells.

What made Macchiarini to think that BM-derive stem cells in the tissue engineered organ can play any role? The first possible mechanism is differentiation of stem cells into airway epithelium and chondrocytes. As of today, there is no any evidence for this mechanism. The second possible mechanism is paracrine (indirect), where BM stem cells serve as a source of growth factors for in situ graft remodeling and regeneration. There is no solid prove for this mechanism as well, because other than stem cells within BM mononuclear cell fraction can do this job. The first candidate for stimulation of in situ regeneration is monocytes. Other leukocytes from BM can provide paracrine, angionetic signals and mobilize endogenous stem/ progenitor cells from bone marrow. Therefore, epithelization and vascularization of engineered trachea in situ, which was observed by Macchiarini, is not a proof of BM-derived stem cells action.

The most sophisticated models of hollow organ tissue engineering use ex vivo seeding with differentiated cells, for example, epithelium, endothelium, smooth muscle and chondrocytes (see examples here and here). However, the value of such seeding remain unclear. Usually pre-seeded cells get cleared rapidly after implantation:

Although the construct supported reepithelialization, stem cell-derived chondrocytes failed to engraft in the heterotopic environment and represent a focus of future investigations.

Overall, the field is lacking of experimental transplantation data of tissue engineered trachea. Very few attempts to do it in large animal model suffered a lack of success (see here and here).

Based on available data, one may ask: “Do we need to seed these engineered hollow organs with any cells at all? Well, we don’t know for sure, but probably not. In fact, the right matrix alone would allow nature to take over and do all regenerative job. There are few good examples to support this concept. First is success of Humacyte – a company, which commercializes decellularized blood vessels. Their experimental studies showed that implanted decellulariized vein alone stimulates neotissue regeneration in situ. Another very recent example is clinical case of eshophageal reconstruction, published in Lancet.

Macchiarini was not the only one, who used stem cell label to hype his research. Another famous trachea surgeon – Martin Birchall, used very similar “stem cell branded” technique in his case report. And many many other surgeons and physicians made names on it. But most of their claims may have nothing to do with biology. Those tissue engineers, who did a lot of animal experiments, would not exploit “stem cell brand” (see Breuer). The lack of understanding and poor experimental work could mislead the public and peers.

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