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Reference:  Jae-Sung Bae, et al, BM-MSC Promote Neuronal Networks with Functional Synaptic Transmission After Transplantation into Mice with Neurodegeneration. Stem Cells 2007;24:1307-16.

Summarized by: Rachid Hamid and Jessica Thomas, Fall 2007

LAY SUMMARY

Bone marrow derived mesenchymal stem cells (BM-MSCs) are stem cells found in the bone marrow and have the potential of differentiation into various cell types provided with optimal conditions. Differentiation is a process by which stem cells are naturally or experimentally transformed into other cell types that possess specialized function such as neural cells that are found in the nervous system.  It has been hypothesized that MSCs cells would be able to differentiate and give rise to neural cells within the brain (1). Researchers believe that by transplanting these cells into damaged tissues may act as an innovative treatment by reversing the damage. One such neurodegenerative disorder is Niemann-Pick Disease type C (NP-C).  NP is an inherited metabolic disorder characterized by accumulation of lipids in the brain due to a defect in cholesterol transport between brain cells (2).

In this particular study, the scientists isolated MSCs from the bone legs of NP-C mice and transplanted them into different groups of NP-C mice in the cerebellum which is a region in the brain associated with motor output and sensory perception (see brain cartoon).  They also used 3T3 cells as a control which was also transplanted into a different group of mice along with a sham transplanted group.  The use of these various groups of transplanted animals will allow comparing and contrasting the outcomes of the experimental work and their significance.  Several experimental tools were used to analyze the samples to prove the authors hypothesis.  The authors were able to demonstrate that transplanting MSC into NP-C mice provided significant changes at the molecular and functional levels in one of the groups that received the MSC cells as compared to the other groups.  These changes are highlighted by the improved balance and coordination observed in those animals which is a significant accomplishment.
 
Unfortunately the results of this study concluded that the fusion between MSCs and damaged neurons rather than, hoped for, cellular differentiation was behind the improved symptoms of some of the mice.  Although the findings were interesting, they would have been more convincing if minor details were not overlooked.  First, one of the risks working with 3T3 cells is the potential of uncontrollable growth and the possibility of undesirable cancerous activity.  Second, the article lacked sufficient evidence of MSCs identity.  It is crucial to isolate and identify the proper cell of interest for subsequent use in transplant studies.  Third, the authors failed to address the long term stability and function of fused MSC. The mice received transplants at 3 weeks of age and were sacrificed 2-4 weeks later. This is far short from the life expectance of laboratory mice of up to two years where the possibility of side effects might appear. 

http://en.wikipedia.org/wiki/Mesenchymal_stem_cell

http://www.ninds.nih.gov/disorders/niemann/niemann.htm

SCIENTIFIC SUMMARY

The goal of this summary is to present the authors’ evaluation of the therapeutic potential of bone-marrow-derived mesenchymal cells (BM-MSC) in neurodegenerative disease, using the Niemann-Pick type C mouse (NP-C) model. NP is an inherited metabolic disorder characterized by the accumulation of lipids in the brain, due to a defect in cholesterol transport among brain cells (1).  The flow chart summarizes the methods and techniques uses in the study.

MSCs were isolated from tibias and femurs of NP-C mice heterozygous for DsRed/Phgdh and characterized for cluster differentiation CD29/CD90+ and for CD34/CD45/CD117-.  At 3 weeks of age BM-MSCs were transplanted into the cerebellums {see brain cartoon} (2) of NP-C mice and NP-C GsbsGFP+.  3T3 fibroblasts cells and sham transplanted animals were used as assay controls.

Microarray analysis showed a differential gene expression among the test groups at 2 and 4 week time points post transplantation.  Subsequent evaluation of genes of interest using quantitative real time polymerase chain reaction (qPCR) proved increased expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, Gamma-aminobutyric acid (GABA) receptors, myelin and glutamate decarboxilase.  All of which have been associated with neurotrasmission in the cerebellum.   MSC transplanted animals showed increased numbers of purkinje neurons in their cerebellums and improved Rota-Rod test outcomes for balance and coordination and deceased lipid accumulation as compared to 3T3 and sham transplanted animals.  Transplanted animals showed slight decrease in brains size as compared to normal animals. However, this decrease was insignificant.  The electrophysiology evaluation, the most interesting finding in this study, the authors were succesful in proving that GFP+/DsRed+ (from NP-C GFP+ mice transplanted with BM-MSC DsRed+ cells) purkinje cells respond to depolarizing current pulses. These findings contrast the results of DsRed positive cells.  This indicated that BM-MSC undergone fussion with purkinje neurons rather than transdifferentiation.

Although the author’s findings were interesting, they would have been more convincing if minor details were not overlooked as stated below.

 The author’s characterization of BM-MSC was insufficient by including only CD29/CD90 as positive and CD34/CD45/CD117 as negative markers fro selection.  It would be more credible and interesting if the isolated mouse BM-MSC expressed Oct-4 and Rex-1 (3) or flowcytometry supporting data was done and included.

3T3 are immortalized fibroblasts cells originally isolated from mouse embryos might not be the most ideal control to use.  The authors could have differentiated the BM-MSC invitro into fibroblasts and used in the transplant instead of 3T3.  This will serve two purposes.  First, showing that the BM-MSCs are true stem cells as an additional proof.  Second, the use of BM-MSC derived fibroblasts would allow for a meaningful comparison to BM-MSC.

The authors failed to address the long term stability and function of fusion by BM-MSC with neural cells.  The mice received transplants at 3 weeks of age and were sacrificed 2-4 weeks later. Far short from the life expectance of laboratory mice of up to two years.  

References

• www.ninds.nih.gov/disorders/niemann/niemann.htm
• www.learn.genetics.utah.edu/.../neurobiol.cfm
• Lamoury FMJ, Croitoru-Lamoury J, Brew BJ. Undifferentiated mouse mesenchymal stem cells spontaneously express neural and stem cell markers Oct-4 and Rex-1. Cytotherapy. 2006; 8:228-42.

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