Continuous BDNF Supply by Stem Cells May Have Therapeutic Potential

Vanda Pinto, PhD avatar

by Vanda Pinto, PhD |

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MeCP2 Rett syndrome | Rett Syndrome News | illustration of lab mice

Stem cells engineered to produce a constant level of a downstream target of the MECP2 protein, called brain-derived neurotrophic factor (BDNF), increased the development of new neurons and prevented body weight loss in a mouse model of Rett syndrome.

The study with that finding, “Brain-Derived Neurotrophic Factor Secreting Human Mesenchymal Stem Cells Improve Outcomes in Rett Syndrome Mouse Models,” was published in the journal Frontiers in Neuroscience.

Rett syndrome is caused mostly by a deficiency in the MECP2 protein, known to activate or silence many genes that are essential for brain function and development. BDNF is a target gene of MECP2, and studies have reported that it is downregulated (lower activity) in the brain, blood, and cerebrospinal fluid — the liquid surrounding the brain and spinal cord — in animal models of Rett.

Preclinical studies investigating therapeutic approaches for Rett have included the direct administration of MECP2 and BDNF for the relief of symptoms. However, recombinant (lab-made) forms of BDNF do not stay in the bloodstream for very long and their diffusion through the blood-brain barrier, a protective network of cells that separates the brain from blood vessels, is low.

A team of scientists in South Korea used the gene-editing technology CRISPR/Cas9 to generate stem cells with the ability to produce a continuous and higher than normal BDNF supply. The engineered stem cells then were injected in the brain of a mouse model of Rett, and the effects on body and brain weights, nerve cell numbers, and the number of synapses, were evaluated. Notably, synapses are the junctions between two nerve cells that allow them to communicate.

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First, stem cells derived from human umbilical cord blood were cultured. The researchers used the CRISPR/Cas9 system to manipulate the cells genetically and insert a vector with the instructions for BDNF. These new cells, called BDNF-MSCs, as well as stem cells treated with lab-made BDNF, then were exposed to a PTP1B  inhibitor. Of note, PTP1B blocks TRKB, a major BDNF receptor. Inhibiting PTP1B is meant to prevent the weakening of BDNF signaling.

In cells where MECP2 was silenced, the levels of the activated form of two molecules associated with BDNF signaling — pAKT and pERK — were decreased, as were those of pp38 (inhibited by MECP2 in its cell multiplication effect) compared to control cells. However, after using a PTP1B blocker,  both BDNF-treated and BDNF-MSC-treated cells showed increases in pAKT and pERK, and decreases in pp38.

Next, the potential therapeutic effects of BDNF-MSCs were assessed in a Rett mouse model (lacking MECP2). BDNF-MSCs were administered directly into the brain, and PTP1B was injected in the abdominal cavity.

Mice lacking MECP2 lost weight over time, unlike the BDNF-MSC-treated animals. In fact, the results showed that mice given BDNF-MSC had the largest brain size and brain weight.

The number of nerve cells were counted in several regions of the brain. In the hippocampus, an area key for learning and memory, BDNF-MSCs-treated mice had the highest number of neurons (44.3), followed by BDNF-treated mice (40.7), and animals without MECP2 (36.3).

“These results suggest that RTT [Rett] induced a reduction in the number of neurons and the neurogenesis [neuron formation] in the hippocampus,” the scientists wrote. “BDNF-MSC treatment was more efficient than the injection of the recombinant form of the protein.”

However, these numbers of nerve cells tended to improve in the presence of BDNF in mice with no MECP2.

Similar to the findings in the hippocampus, the numbers of neurons also were increased in the cortex and striatum — brain regions involved in diverse cognitive processes — when given lab-made BDNF or BDNF-MSCs. These stem cells also increased the number of synapses.

Ultimately, the researchers found that treatment with stem cells delivering BDNF increased pAKT and pERK, and decreased pp38 expression in the brains of the Rett mouse model.

“These results suggest that a continuous in vivo expression of BDNF could have better therapeutic effects, for improving the growth and functional activity of neurons during the [development] of RTT,” the investigators wrote.

“[Although] further studies are required for ascertaining the safe and effective dosage of BDNF-MSC and methods for delivering BDNF-MSC, [this] treatment is a promising therapeutic strategy for treating RTT,” they added.