Cerebrospinal fluid from Alzheimer’s disease patients as an optimal formulation for therapeutic application of mesenchymal stem cells in Alzheimer’s disease

Mesenchymal stem cells (MSCs) are safe, and they have good therapeutic efficacy through their paracrine action. However, long-term culture to produce sufficient MSCs for clinical use can result in side-effects, such as an inevitable senescence and the reduction of the therapeutic efficacy of the MSCs. In order to overcome this, the primary culture conditions of the MSCs can be modified to simulate the stem cells’ niche environment, resulting in accelerated proliferation, the achievement of the target production yield at earlier passages, and the improvement of the therapeutic efficacy. We exposed Wharton’s jelly-derived MSCs (WJ-MSCs) to pressure stimuli during the primary culture step. In order to evaluate the proliferation, stemness, and therapeutic efficacy of WJ-MSCs, image, genetic, and Western blot analyses were carried out. Compared with standard incubation culture conditions, the cell proliferation was significantly improved when the WJ-MSCs were exposed to pressure stimuli. However, the therapeutic efficacy (the promotion of cell proliferation and anti-apoptotic effects) and the stemness of the WJ-MSCs was maintained, regardless of the culture conditions. Exposure to pressure stimuli is a simple and efficient way to improve WJ-MSC proliferation without causing changes in stemness and therapeutic efficacy. In this way, clinical-grade WJ-MSCs can be produced rapidly and used for therapeutic applications.

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“…The differentiation of the WJ-MSCs was tested according to the procedure outlined in a previous report [ 49 ].…”

Section: Methodsmentioning

confidence: 99%

Pressure Stimuli Improve the Proliferation of Wharton’s Jelly-Derived Mesenchymal Stem Cells under Hypoxic Culture Conditions

Park

Kim

Kwon

et al. 2020

IJMS

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“…Human Warton’s jelly-derived MSCs from a single donor at passage 5–6 were used in this study. Stemness of MSCs was confirmed using in vitro differentiation assays into osteogenesis, adipogenesis, and chondrogenesis and flow-cytometric analysis for cell surface markers (CD73, CD90, CD105, CD166, CD14, CD11b, HLA-DR (MHCII), CD34, CD45, and CD19), as described previously [39]. After getting 90% confluence, MSCs were preconditioned with thrombin (2 U/mL; Sigma–Aldrich, Steinheim, Germany) in culture medium (α-MEM; Gibco, Life Technologies, Carlsbad, CA, USA) for 3 h. Control naïve MSCs were prepared in the same manner except for the thrombin treatment.…”

Section: Methodsmentioning

confidence: 99%

Thrombin Preconditioning Enhances Therapeutic Efficacy of Human Wharton’s Jelly–Derived Mesenchymal Stem Cells in Severe Neonatal Hypoxic Ischemic Encephalopathy

Kim

Sung

Chang

et al. 2019

IJMS

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We investigated whether thrombin preconditioning of human Wharton’s jelly–derived mesenchymal stem cells (MSCs) improves paracrine potency and thus the therapeutic efficacy of naïve MSCs against severe hypoxic ischemic encephalopathy (HIE). Thrombin preconditioning significantly enhances the neuroprotective anti-oxidative, anti-apoptotic, and anti-cytotoxic effects of naïve MSCs against oxygen–glucose deprivation (OGD) of cortical neurons in vitro. Severe HIE was induced in vivo using unilateral carotid artery ligation and hypoxia for 2 h and confirmed using brain magnetic resonance imaging (MRI) involving >40% of ipsilateral hemisphere at postnatal day (P) 7 in newborn rats. Delayed intraventricular transplantation of 1 × 105 thrombin preconditioned but not naïve MSCs at 24 h after hypothermia significantly enhanced observed anti-inflammatory, anti-astroglial, and anti-apoptotic effects and the ensuing brain infarction; behavioral tests, such as cylinder rearing and negative geotaxis tests, were conducted at P42. In summary, thrombin preconditioning of human Wharton’s jelly-derived MSCs significantly boosted the neuroprotective effects of naïve MSCs against OGD in vitro by enhancing their anti-oxidative, anti-apoptotic, and anti-cytotoxic effects, and significantly attenuated the severe HIE-induced brain infarction and improved behavioral function tests in vivo by maximizing their paracrine anti-inflammatory, anti-astroglial, and anti-apoptotic effects.

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“…First, since the cerebrospinal fluid (CSF) flows along the surface of the spinal cord up towards the brain, MSCs can be delivered into the entire neuraxis. One of our previous studies showed that the CSF from normal elderly or Alzheimer patients does not affect the stemness of MSCs [22]. Thus, we expect that the therapeutic potential of the MSCs will not be affected when injected via the intrathecal route.…”

Section: Introductionmentioning

confidence: 91%

Intrathecal Injection in a Rat Model: A Potential Route to Deliver Human Wharton’s Jelly-Derived Mesenchymal Stem Cells into the Brain

Kim

Lee

et al. 2020

IJMS

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Mesenchymal stem cells (MSCs) are considered as promising therapeutic agents for neurodegenerative disorders because they can reduce underlying pathology and also repair damaged tissues. Regarding the delivery of MSCs into the brain, intravenous and intra-arterial routes may be less feasible than intraparenchymal and intracerebroventricular routes due to the blood–brain barrier. Compared to the intraparenchymal or intracerebroventricular routes, however, the intrathecal route may have advantages: this route can deliver MSCs throughout the entire neuraxis and it is less invasive since brain surgery is not required. The objective of this study was to investigate the distribution of human Wharton’s jelly-derived MSCs (WJ-MSCs) injected via the intrathecal route in a rat model. WJ-MSCs (1 × 106) were intrathecally injected via the L2-3 intervertebral space in 6-week-old Sprague Dawley rats. These rats were then sacrificed at varying time points: 0, 6, and 12 h following injection. At 12 h, a significant number of MSCs were detected in the brain but not in other organs. Furthermore, with a 10-fold higher dose of WJ-MSCs, there was a substantial increase in the number of cells migrating to the brain. These results suggest that the intrathecal route can be a promising route for the performance of stem cell therapy for CNS diseases.

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Cerebrospinal fluid from Alzheimer’s disease patients as an optimal formulation for therapeutic application of mesenchymal stem cells in Alzheimer’s disease

Cited by 15 publications

References 40 publications

Pressure Stimuli Improve the Proliferation of Wharton’s Jelly-Derived Mesenchymal Stem Cells under Hypoxic Culture Conditions

Pressure Stimuli Improve the Proliferation of Wharton’s Jelly-Derived Mesenchymal Stem Cells under Hypoxic Culture Conditions

Thrombin Preconditioning Enhances Therapeutic Efficacy of Human Wharton’s Jelly–Derived Mesenchymal Stem Cells in Severe Neonatal Hypoxic Ischemic Encephalopathy

Intrathecal Injection in a Rat Model: A Potential Route to Deliver Human Wharton’s Jelly-Derived Mesenchymal Stem Cells into the Brain

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