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The latest news and information about what's going on with SCI science and research. Brought to you by Sam Maddox, author of the Christopher & Dana Reeve Foundation Paralysis Resource Guide.

Chinese Repair Cord With Engineered Cells And Scaffold

 Gross morphology and cavity formation of spinal cord tissue dissected at 8 weeks post-operation.Chinese scientists report that they fixed a completely cut spinal cord in lab animals. That is the gist of a spinal cord injury regeneration research publication in the open-access journal PLOS-One that caught my attention this week.

Tissue-Engineered Regeneration of Completely Transected Spinal Cord Using Induced Neural Stem Cells and Gelatin-Electrospun Poly (Lactide-Co-Glycolide)/Polyethylene Glycol Scaffolds”  is from a group of scientists at Sun Yat-Sen University, Guangzhou, China. Rats with 2mm gaps removed from their spinal cords (at T10) recovered significantly when a special scaffold seeded with engineered stem cells was implanted at the injury site.

Photo at right courtesy of PLOS: Gross morphology and cavity formation of spinal cord tissue dissected at 8 weeks post-operation.
 
It’s quite a complex surgical process, all the more so because of so much bio-engineering – first by taking embryonic fibroblasts from the mice and using a retrovisus to convert them into neural stem cells. Second, by creating a three dimensional scaffold from two biodegradable polymers, PLGA and PEG. And third, by implanting the scaffold into the gap of a transected spinal cord.
 
From the paper:
 
Tissue engineering has brought new possibilities for the treatment of spinal cord injury. Two important components for tissue engineering of the spinal cord include a suitable cell source and scaffold. In our study, we investigated induced mouse embryonic fibroblasts (MEFs) directly reprogrammed into neural stem cells (iNSCs), as a cell source. Three-dimensional electrospun poly (lactide-co-glycolide)/polyethylene glycol (PLGA-PEG) nanofiber scaffolds were used for iNSCs adhesion and growth.
 

The scientists report that the transplanted stem cells survived, grew robustly, and took on the form and function of nerve cells.
 
Results indicated that iNSCs showed similar morphological features with wild-type neural stem cells (wt-NSCs), and expressed a variety of neural stem cell marker genes. Furthermore, iNSCs were shown to survive, with the ability to self-renew and undergo neural differentiation into neurons and glial cells within the 3D scaffolds in vivo. The iNSC-seeded scaffolds restored the continuity of the spinal cord and reduced cavity formation. Additionally, iNSC-seeded scaffolds contributed to functional recovery of the spinal cord.
 

The researchers like embryonic stem cells, but they are controversial. They like induced pluripontent (reverse engineered) stem cells, but they have potential to form teratomas (excessive growth).
 
From the paper:
 
.... NSCs are the most widely used for SCI with broad development prospects. Many studies on NSC transplantation have shown that, besides supplementing the loss of neurons and glial cells, NSCs may also play other roles during the promoting of the formation of new myelin. Currently, various techniques are reported for obtaining NSCs, such as differentiation from embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) and direct isolation from embryonic or adult mammal central nervous systems (CNS). However, these approaches are non-viable owing to ethical issues or potential tumorigenic risks. In our study, we induced mouse embryonic fibroblasts (MEFs) by directly reprogramming them into NSCs. According to extensive previous studies, this method for obtaining NSCs not only avoids ethical issues and tumorigenic risks, but is also more simple and efficient compared with other techniques.
 
Theoretically, under optimum conditions, stem cells can differentiate into required cells to replace those that are lost. A variety of stem cells have been used in CNS [central nervous system] repair, including ESCs [embryonic stem cells] , NSCs [neural stem cells] and bone marrow mesenchymal stem cells (MSCs). A number of studies indicate that NSCs are a suitable choice for the treatment and replacement of injured spinal cord. NSCs can efficiently differentiate into neurons, astrocytes and oligodendrocytes. Furthermore, owing to their low immunogenicity profile, NSCs do not cause obvious graft rejection after transplantation.
 
In our study, we induced Sox2-transfected MEFs through direct reprogramming into neural stem cells on low-attachment surfaces. On the 7th day of induction, expression of NSC-related genes increased dramatically compare to original cells, which was similar to wt-NSCs. Furthermore, the lack of pluripotent-related gene expression in the iNSCs suggested that direct conversion of fibroblasts into iNSCs did not undergo an intermediate stage into ESCs. Furthermore, iNSCs exhibited a similar morphology to wt-NSCs, and were able to differentiate into neurons and glial cells in vitro. In addition, after transplantation of iNSCs-seeded 3D scaffolds into rats, cells were observed to survive and differentiate into neurons and glial cells. Notably, iNSCs have no ethical controversy attached to them, and are less likely to cause teratomas. In conclusion, iNSCs are the perfect cell substitute for CNS cell therapy, when compared with ESCs and iPSCs-derived NSCs.


Making the 2mm-long scaffold structure introduced another complex engineering variable. From the paper:
 
A biocompatible and biodegradable scaffold is key for tissue engineering to treat SCI. Poly (lactic-co-glycolic acid) (PLGA) is one of the few biomaterials approved by the United States Food and Drug Administration for experimental and clinical application. It has been widely used as an artificial catheter, drug control-released carrier and tissue engineering scaffold material. PLGA is one of the top biodegradable synthetic polymers used for tissue engineering owing to the ease of controlling its mechanical properties and biodegradation.
 
In our study, we synthesized an electrospun PLGA-PEG biomaterial and tested its ability to promote adhesion, proliferation and neurite outgrowth of iNSCs in vitro. The results indicated that the PLGA-PEG nanofibers scaffold was superior for iNSC adhesion and proliferation compared with the PLGA scaffold. Furthermore, the PLGA-PEG scaffolds showed no obvious cell toxicity.

How did it do in the animals? The PLGA-PEG combination improved scores on the BBB scale from zero at injury to about 18 (based on a 21 point scale). That’s pretty meaningful recovery.

Ready for human trials? No. The induction process to make mature cells embryonic-like is not safety-ready for the clinic. The implantable scaffold idea is not fully embraced by the neurosurgeon community but it is already being tried in clinical trials from the Boston biotech company InVivo (two acute SCI patients so far have gotten the company’s implant scaffold; the company has suggested over the years that it could seed its scaffold with stem cells, as the Chinese have, to be used in chronic SCI).

Interestingly, the same day I saw the PLOS-One paper from China, I saw a report in the Washington Post about fraud in scientific publishing – 43 papers had to be retracted from a single journal because the peer review process had been scammed. All 43 were papers from China. I certainly don’t mean to tar the SCI study with the same brush but you have to wonder about high pressure, competitive science and the peer review system -- not just in China either. No room here but if you’re interested in the integrity of the literature publication process, click here.

 
Posted by Community Admin on Mar 31, 2015 7:24 PM America/New_York

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