MSC-CM Potential for Parkinson’s disease treatment

Parkinson’s disease is a slow-progressing neurological disorder that leads to the gradual death of nerve cells in the brain, resulting in symptoms such as tremors, stiffness, difficulty in movement, and impaired balance. Globally, disability and mortality due to Parkinson’s disease are increasing more rapidly than any other neurological disorder, doubling in the past 25 years. According to the World Health Organization’s 2019 estimates, over 8.5 million people suffer from Parkinson’s disease. Among them, around 5.8 million people are living with disabilities, marking an 81% increase since 2000 and causing 329,000 deaths, which has risen by over 100% since 2000  [1].

Causes of Parkinson’s Disease

The fundamental mechanisms of Parkinson’s are still not entirely clear; however, both environmental and genetic factors contribute to its pathogenesis [2, 3]. Initially, mutations linked to Parkinson’s were associated with α-synuclein; subsequently, various gene mutations, most notably PINK1, DJ-1, LRRK2, and Parkin, have been identified [4]. The main cause of Parkinson’s is the loss of dopaminergic nerve cells in the central nervous system, the primary factor behind motor symptoms. Dopamine metabolism, neuroinflammation, dysfunction of the autophagic-lysosomal pathway, oxidative stress, and protein aggregation are associated with the gradual loss of dopaminergic nerve cells. Additionally, researchers have found changes in pro-inflammatory cytokines, including IFN-γ, TNF-α, IL-6, and IL-1β, in the immune system related to the brain and cerebrospinal fluid of post-mortem Parkinson’s patients [5]. Environmental factors such as exposure to toxins, head injuries, and smoking are potential risk factors for the disease. Other factors as age, gender, and cultural factors, may also influence disease development. However, researchers need to conduct more studies to gain a comprehensive understanding of the causes of Parkinson’s disease.

Potential of MSC-CM Therapy in Parkinson’s Treatment

The recent surge in Parkinson’s cases has raised concerns for patients and the community, especially since there is no effective cure. Currently, researchers consider stem cell therapy as a new treatment method that they believe can reduce neuroinflammation, regulate the immune system, and replace or repair dopamine-producing cells lost or damaged in the brains of Parkinson’s patients [6]. This treatment approach holds great promise and is easily accessible to patients. However, scientists point out that the therapeutic mechanism of stem cells operates through paracrine signaling. This means that researchers can culture stem cells in the laboratory to make them secrete soluble factors or package them in extracellular vesicles. The conditioned medium from the culture of mesenchymal stem cells (MSC-CM) contains various factors, such as growth factors, cytokines, and other signaling molecules that can influence cell activities [7].

Extensive research has shown promising results in the efficacy of MSC-CM in treating Parkinson’s disease. Notably, studies have described the positive impacts of MSC-CM in Parkinson’s disease. In vitro studies have demonstrated the neuroprotective effects of substances derived from MSCs and dental pulp stem cells in SH-SY5Y cells treated with 6-hydroxydopamine (6-OHDA–a widely used neurotoxin to create Parkinson’s disease models) and differentiated nerve stem cells in mice [8]. Another research group investigated the viability of dopaminergic cells from different sources when treated with MSC-CM originating from mouse bone marrow, revealing that prostaglandin E2 receptors represent a key factor in neuroprotective events [9].

An intriguing study assessed the neuroprotective effects of adipose-derived mesenchymal stem cell (ASC)-CM on the gene expression of nourishing nerve cells and the density of TH+ cells in mice injured by 6-OHDA. ASC secretes various neurotrophic factors and cytokines in CM, providing neuroprotection through antioxidant and nutritional effects. ASC-CM protects dopaminergic nerve cells by preserving TH+ nerve cells and increasing the expression of BDNF (Brain-Derived Neurotrophic Factor, a crucial protein in the development of nerve connections) and neurotrophin-3 [10]. BDNF is essential for the survival of nerve cells in the central nervous system [11]. The ability of MSC-CM to reduce extracellular α-synuclein, both in vitro and in living organisms, has also been reported, primarily through the mediation of matrix metalloproteinase-2 [12].

An interesting study using a Parkinson’s mouse model compared the transplantation of human bone marrow-derived stem cells (hBMSCs) with hBMSC-CM. hBMSC-CM could protect dopaminergic nerve cells when compared to hBMSC alone and improved mouse activities. Moreover, hBMSC-CM had a greater impact on the differentiation and survival of nerve cells in an in vivo model. This study provides valuable insights into the potential use of hBMSC-CM as a therapeutic tool for Parkinson’s disease [13].

More recently, another research group compared the therapeutic efficacy of stem cells with their conditioned environment in a rotenone-induced Parkinson’s mouse model, particularly using bone marrow-derived mesenchymal stem cells (BMSCs). Biochemical, histological, and immunohistochemical parameters significantly improved in both the BMSC and BMSC-CM treated groups. Interestingly, BMSC-CM appeared to almost reset the normal histological structure of the central nervous system [14]. Mesenchymal stem cells from dental pulp in MSC-CM show promising potential in regenerative medicine. Specifically, Chen and colleagues investigated the therapeutic efficacy of MSC-CM derived from dental pulp in a rotenone-induced Parkinson’s mouse model.

Notably, CM derived from dental pulp could improve motor function in Parkinson’s mice, reduce neuroinflammation, increase TH+ cell density, and decrease central nervous system α-synuclein levels [14]. Thus, researchers consider MSC-CM treatment using stem cells as an effective alternative therapy for Parkinson’s [15, 16]. Yao and colleagues reported that using MSC-CM for treating Parkinson’s in a mouse model resulted in improved motor and cognitive functions related to increased cell survival and differentiation of dopaminergic nerve cells in the mouse substantia nigra [17].

Although several clinical trials have been completed or are underway to explore the transplantation of stem cells from various sources for Parkinson’s treatment (NCT02611167; NCT02780895; NCT05152394; NCT01446614; NCT03684122), no registered trial has evaluated the safety and efficacy of MSC-CM on Parkinson’s patients. Overall, the effects of MSC-CM on Parkinson’s from preclinical studies strongly suggest numerous possibilities for further research, testing, and potential real-world applications of MSC-CM. Further research is necessary to determine the long-term effectiveness of stem cell therapy for Parkinson’s, as it is still considered experimental.

References:

1. WHO, https://www.who.int/news-room/fact-sheets/detail/parkinson-disease. 2022.
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