Dual Effects of Human Placenta-Derived Neural Cells on Neuroprotection and the Inhibition of Neuroinflammation in a Rodent Model of Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease in the elderly and the patients suffer from uncontrolled movement disorders due to loss of dopaminergic (DA) neurons on substantia nigra pars compacta (SNpc). We previously reported that transplantation of human fetal midbrain-derived neural precursor cells restored the functional deficits of a 6-hydroxy dopamine (6-OHDA)-treated rodent model of PD but its low viability and ethical issues still remain to be solved. Albeit immune privilege and neural differentiation potentials suggest mesenchymal stem cells (MSCs) from various tissues including human placenta MSCs (hpMSCs) for an alternative source, our understanding of their therapeutic mechanisms is still limited. To expand our knowledge on the MSC-mediated PD treatment, we here investigated the therapeutic mechanism of hpMSCs and hpMSC-derived neural phenotype cells (hpNPCs) using a PD rat model. Whereas both hpMSCs and hpNPCs protected DA neurons in the SNpc at comparable levels, the hpNPC transplantation into 6-OHDA treated rats exhibited longer lasting recovery in motor deficits than either the saline or the hpMSC treated rats. The injected hpNPCs induced delta-like ligand (DLL)1 and neurotrophic factors, and influenced environments prone to neuroprotection. Compared with hpMSCs, co-cultured hpNPCs more efficiently protected primary neural precursor cells from midbrain against 6-OHDA as well as induced their differentiation into DA neurons. Further experiments with conditioned media from hpNPCs revealed that the secreted factors from hpNPCs modulated immune responses and neural protection. Taken together, both DLL1-mediated contact signals and paracrine factors play critical roles in hpNPC-mediated improvement. First showing here that hpMSCs and their neural derivative hpNPCs were able to restore the PD-associated deficits via dual mechanisms, neuroprotection and immunosuppression, this study expanded our knowledge of therapeutic mechanisms in PD and other age-related diseases.

Mesenchymal stem cells: Cell therapy and regeneration potential

“…Stem cell‐based therapies can greatly impact the field of regenerative medicine. MSCs have been used in preclinical and clinical studies to treat degenerative diseases, such as AD (Cui et al, ; Han et al, ; J. Shin et al, ; X. Wang, Ma, et al, ), DDD (Ahn et al, ; Beeravolu et al, ; Pereira et al, ; Perez‐Cruet et al, ), MS (Harris et al, ; Nasri et al, ; Planchon et al, ), PD (Jamali et al, ; H. Kim, Lee, et al, ), and RDD (Mead, Amaral, & Tomarev, ), as summarized in Table . The regenerative mechanisms of transplanted MSCs for these diseases are still unclear; however, some reports have suggested that MSCs have the potential to differentiate or have paracrine effects in vivo (Lee, Choi, Cha, & Hwang, ).…”

“…MSCs have been used in preclinical and clinical studies to treat degenerative diseases, such as AD (Cui et al, 2017;Han et al, 2018;X. Wang, Ma, et al, 2018), DDD (Ahn et al, 2015;Beeravolu et al, 2018;Pereira et al, 2016;Perez-Cruet et al, 2018), MS (Harris et al, 2018;Nasri et al, 2018;Planchon et al, 2018), PD (Jamali et al, 2018;H. Kim, Lee, et al, 2018), and RDD (Mead, Amaral, & Tomarev, 2018), as summarized in Table 2.…”

“…In addition, MSCs have a paracrine effect that promotes immunomodulation as well as antiapoptotic and anti-oxidative effects, which can be helpful for treating neuromuscular pains (van Buul et al, 2014) and many other diseases (de Witte et al, 2018;Francois et al, 2013;Khubutiya, Vagabov, Temnov, & Sklifas, 2014). MSCs are also being investigated for their therapeutic potential to treat degenerative diseases and disorders such as Parkinson's disease (PD; Jamali, Ma Hattab, Amman, & Awidi, 2018; H. Kim, Lee, et al, 2018), Alzheimer's disease (AD; Cui et al, 2017;Han et al, 2018), amyotrophic lateral sclerosis (Bonafede & Mariotti, 2017), multiple sclerosis (MS; Harris et al, 2018; Nasri Ahn et al, 2015;Beeravolu et al, 2018;Perez-Cruet et al, 2018), retinal degenerative disease (RDD; Y. Wang, Zhang, Shen, Zhang, & Gu, 2018;, myocardial infarction (X. Q.…”

“…Baek et al, 2011;X. Q. Chen et al, 2014) Pain(van Buul et al, 2014) Parkinson's disease(Jamali et al, 2018;H. Kim, Lee, et al, 2018) Retinal diseases (Y Wang, Zhang, et al, 2018;.…”

Neural stem cell secretome and its role in the treatment of neurodegenerative disorders

“…For example, transplanted neural progenitor cells (NPCs) can play a bystander effect of neural protection and immune regulation in addition to the role of cell replacement, thus promoting tissue repair by prevention of tissue damage, interfering with pathogenic processes, or saving endogenous nerve cells (De Feo et al, 2012). Additionally, different studies have confirmed other bystander effects induced by NSCs, such as ameliorating damage to neurophysical structures, immunoregulation (Kim et al, 2018) , neuroprotection (Cui et al, 2015;Pang et al, 2017), neurotrophication (Bernstock et al, 2017;Marsh and Blurton-Jones, 2017) and angiogenesis (Boese et al, 2018), as well as by having an endogenous impact in disease models (Jablonska et al, 2016) .…”