Protein From Stem Cells Triggers Nerve Cell Repair in Mouse Model

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by Steve Bryson PhD |

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A protein secreted by stem cells, known as pentraxin 3 (PTX3), promoted the repair of nerve cells damaged as a consequence of Parkinson’s disease in a mouse model, a study reported.

These findings support further work into PTX3 as a potential therapy to slow or halt disease progression, its researchers noted.

The study, “Pentraxin 3 secreted by human adipose-derived stem cells promotes dopaminergic neuron repair in Parkinson’s disease via the inhibition of apoptosis,” was published in the FASEB Journal.

Dopaminergic neurons are nerve cells in the brain that produce dopamine, a chemical messenger that controls balance and movement and is also involved in cognition, memory, learning, sleep, and mood. In Parkinson’s, these dopaminergic neurons are damaged and lost, leading to a drop in dopamine levels and symptoms of the disease.

Mesenchymal stem cells (MSCs) are a type of adult stem cell present in bone marrow, umbilical cords, and fat (adipose) tissue. These cells can self-renew and transform into other cells that are part of bone, muscle, fat, and connective tissue.

Transplantation of MSCs has emerged as a potential Parkinson’s treatment. Human MSCs isolated from adipose tissue (hADSCs) can induce local repair by secreting specific factors that influence surrounding cells. Previous studies in mouse models have demonstrated that transplanting hADSCs into restored damaged dopaminergic neurons in the mice.

PTX3 is a protein that plays a role in acute inflammation and can also block cell apoptosis — the biological process of programmed cell death, in which the body purposely eliminates cells that are unwanted or damaged beyond repair. MSCs derived from bone marrow have been shown to secrete PTX3 and promote wound healing, while PTX3 secreted by MSCs from umbilical cord blood stimulated nerve regeneration.

However, the role of PTX3 in hADSCs in the repair of dopaminergic neurons in Parkinson’s is not fully understood.

Researchers at Southern Medical University in Guangzhou, China, chemically induced Parkinson’s disease in mice and treated them with hADSCs — human MSCs isolated from fat tissue — to determine whether PTX3 is involved in dopaminergic neuron repair.

6-OHDA is a derivative of dopamine that causes the death and degeneration of the dopaminergic neurons when injected into the area of the brain known as the substantia nigra, the region that contains these neurons. Mice selected as a Parkinson’s model walked rapidly in circles, as assessed by the apomorphine (APO)-rotation experiment, a test used to evaluate motor impairment.

hADSCs were then transplanted into the substantia nigra of these mice. Treatment improved body movement such that they covered a greater distance, had a shorter resting time, and fewer rotations than untreated mice. “These data indicated that hADSCs could improve the motor performances in the 6-OHDA-induced [Parkinson’s] mice model,” the researchers wrote.

Analysis of brain tissue revealed that mice treated with hADSCs had increased production of the TH protein, a marker of dopaminergic neurons, and a higher percentage of TH-positive nerve fibers than untreated mice.

Brain slices from young mice were also exposed to 6-OHDA and then treated with hADSCs, which prevented the reduction of TH protein in brain tissue. 6-OHDA-damaged brain slices secreted an enzyme called lactate dehydrogenase, which was blocked by hADSCs treatment, suggesting that “hADSCs could protect the dopaminergic neurons from damage caused by 6-OHDA in an indirect manner,” the team added.

To determine if PTX3 or other factors participate in the protective effect of hADSCs, a series of experiments were also conducted to look for gene and protein activity (expression) after culturing hADSCs with 6-OHDA-treated brain slices. PTX3 was the only protein that showed a difference in expression in all tests.

To confirm these results, mice induced with 6-OHDA were treated with a purified version of the human PTX3 protein, hADSCs, as well as hADSCs treated with a small RNA fragment that selectively reduces PTX3 protein production (si-PTX3).

Motor performance tests found those treated with hADSCs, si-PTX3, and PTX3 protein all showed a greater distance of movement, faster movement speed, shorter resting time, and less rotation than untreated mice. Notably, mice given hADSCs plus si-PTX3, which lowers PTX3, performed less well on the rotation test.

Researchers found that 6-OHDA-damaged brain slices showed a loss of TH-positive dopaminergic neurons in the substantia nigra. Still, treatment with hADSCs and purified PTX3 significantly increased the number of TH-positive cells. Their density was less prominent in the si-PTX3 group compared to the hADSC group.

“These results indicated that PTX3 could mimic the effects of hADSCs in protecting the dopaminergic neurons from 6-OHDA neurotoxicity in mice,” the researchers wrote.

Finally, to investigate how PTX3 exerted its protective effects, brain tissue from 6-OHDA-exposed mice and those subsequently treated was further examined. 6-OHDA’s use increased the levels of enzymes associated with apoptosis, whereas mice treated with hADSCs and purified PTX3 all had lower enzyme levels to a similar extent. hADSC plus si-PTX3 had a partial effect.

“PTX3 could protect the dopaminergic neurons by inhibiting extrinsic apoptosis, akin to the hADSCs,” the scientists wrote. Of note, extrinsic apoptosis is initiated by signals outside the cell.

“This study demonstrated the neuroprotective function of PTX3 secreted by hADSCs on [Parkinson’s disease] mice, indicating that the protective effect of hADSCs on the dopaminergic neurons was partly due to the secretion of PTX3,” the team concluded. “Thus, our study showed the potential of PTX3 in the treatment of [Parkinson’s disease] and provided a novel idea for cell-based treatments.”