Stem Cells from Your Nose to Treat Parkinson’s Disease?


Parkinson’s disease (PD) is a neurodegenerative disease that is a global problem and the incidence of PD increases as the population lives longer and longer. PD results from the loss of dopamine-making neurons in the midbrain. The main treatment for PD is a drug called L-DOPA, which can cross the blood-brain barrier, but this drug decreases in effectiveness as time progresses because the neurons become less sensitive to the drug and L-DOPA does not prevent dopamine-making neurons in the midbrain from dying.

substantia nigra

Experimental stem cell treatments of PD have used embryonic stem cells and induced pluripotent stem cells that were differentiated into dopamine-making neurons and transplanted into the midbrain of rodents that suffered from drug-induced PD. Unfortunately, even though symptom relief was observed, tumors were formed in many of these animals in these experiments. Until a more sure-fire way is discovered to identify and isolated dopamine-secreting neurons from other cells types, this approach will always seem too dangerous for clinical trials. References: Embryonic stem cells – Brederlau, et al., Stem Cells 2006 24:1433-40; Sonntag KC, et al. (2007) Stem Cells 25:411–418. and Roy, et al., Nature Medicine 2006 12:1259-68. Induced Pluripotent Stem Cells – Chang, et al., Cell Transplant 2012 21:313-32.

A paper that used induced pluripotent stem cells and differentiated them into dopamine-producing neurons which were transplanted into the brains of PD rodents did not produce tumors (see Hargus, et al., Proceedings of the National Academy of Sciences USA 2010 107:15921-6). It is likely that the stringent isolation procedures employed in this paper decreased tumor incidence (48 different cell lines were generated in this paper and none of them produced detectable tumors).

These experiments show that stem cell-based treatments for PD are feasible. The key is to find the right cell. Well, an old bromide says that “your nose knows.” Maybe this is true in the case of PD treatments. In the nose resides a tissue known as the “olfactory epithelium,” (OE) which is a source of stem cells that can form neurons. OEs can be harvested with minimally invasive nasal surgery (see Winstead W, et al., American Journal of Rhinology 2005 19:83-90). In fact, more than 150 different patient-specific cell lines of “human olfactory neural progenitor” (hONPs) cells have been established from cultures of adult olfactory epithelial cells taken from cadavers (see Roisen FJ, et al., Brain Research 2001 890:11-22).

 The olfactory epithelium lines the posterodorsal nasal cavity immediately inferior to the cranial cavity. The normal epithelium is composed of a handful of cell types: sustentacular cells (Sus), microvillar cells (a supporting cell variant), olfactory sensory neurons – both mature and immature (OSNs), globose basal cells (GBCs), horizontal basal cells (HBCs), Bowman’s duct and gland cells. Deep to the basal lamina, the fascicles of the olfactory axons are ensheathed by the specialized glia of the olfactory nerve, the olfactory ensheathing cells (OECs). In addition, stromal cells (fibroblasts) of the lamina propria secrete signals that regulate epithelial assembly and turnover.
The olfactory epithelium lines the posterodorsal nasal cavity immediately inferior to the cranial cavity. The normal epithelium is composed of a handful of cell types: sustentacular cells (Sus), microvillar cells (a supporting cell variant), olfactory sensory neurons – both mature and immature (OSNs), globose basal cells (GBCs), horizontal basal cells (HBCs), Bowman’s duct and gland cells. Deep to the basal lamina, the fascicles of the olfactory axons are ensheathed by the specialized glia of the olfactory nerve, the olfactory ensheathing cells (OECs). In addition, stromal cells (fibroblasts) of the lamina propria secrete signals that regulate epithelial assembly and turnover.

Human ONPs can also be differentiated into dopamine-making neurons in culture (Zhang X., et al., Stem Cells 2006 24:434-442). Therefore, these cells should be candidate stem cells for making treatments for PD.

Fred Roisen and his cohorts from the University of Louisville, Kentucky, has used hONPs to treat rats with drug-induced PD.  In their paper, Roisen and others used cultures of hONPs and then proceeded to differentiate them into dopamine-making neurons. Then they transplanted these cells into the midbrains of rats that had been treated with 6-hydroxydopamine, which is a drug that kills off dopamine-making neurons in the midbrain and induces PD. However, it is important to understand that the dopamine-producing neurons were only destroyed on the right side of the brain, thus leaving the left side intact. When they stem cells were injected into the midbrains of these rats, they were only injected into the right side, the side that had been damaged by the drugs. Therefore, the right side of the midbrain served as a control throughout these experiments.

The behavioral tests on these PD rats determined if the transplanted hONPs helped decrease the effects of PD. In all three behavioral tests, the hONP-injected rats showed significant improvements over the untreated rats. Were these improvements due to the formation of new dopamine-making neurons? The answer is a clear yes, since postmortem analyses of the brains of these rats showed that the hONP-injected rats not only showed the presence of dopamine-making neurons on the injected side, but the levels of dopamine production in the right side of the brain as compared to the left side of the brain were higher in the hONP-injected animals, even though they were three times lower than those dopamine levels found in the left side of the midbrain.

This experiment shows that hONPs should be considered serious players in the treatment of PD. In none of the transplanted animals were tumors found. Therefore, hONPs seem to be safe, they are easily acquired, and they have the capacity to form dopamine-making neurons. The goal should be to jack up the dopamine levels in the transplanted cells.

See Meng Wang, Chengliang Lu, Fred Roisen, “Adult human olfactory epithelial-derived progenitors: A potential autologous source for cell-based treatment for Parkinson’s disease,” Stem Cells Translational Medicine 2012 1:492-502.