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Understanding the impact of common medications on neural stem cell functions

Primary Supervisor: Professor Johannes Boltze (neurobiological and stem cell-related aspects)

Secondary supervisor: Dr Robert Dallmann, Associate Professor (pharmacological aspects and in vitro work)

PhD project title: Understanding the impact of common medications on neural stem cell functions

University of Registration: University of Warwick

Project outline:

Background and hypothesis: Neural stem cells (NSCs) than can proliferate and differentiate into neurons and glial cells were identified in the adult human brain1. Their function is not entirely understood but it is believed that NSCs contribute to memory function and small scale repair process in the brain as we age2. Human NSCs are also a tool for regenerative medicine. It was also shown that the cells exert beneficial effects by secretion of paracrine factors, thus acting in a “drug-like” fashion. These processes are relevant for maintaining the steady-state micro-milieu in the brain as well as for regenerative processes following injury.

Medication is a normal element of modern life. Effects of ageing and decreased mobility such as elevated blood pressure or dyslipidaemia can be effectively treated, allowing us to maintain a healthy condition during ageing. Medication is also prevalent for conditions not associated with age-related comorbidities as exemplified by painkillers taken. Medication has become so common that pharmacologists now thoroughly investigate drug-drug-interactions, processes changing the abilities and impact of a drug in presence of another.

While almost nothing is known on drug influences on NSC, those are likely to exist. For instance, some non-steroidal anti-inflammatory drugs (e.g. meloxicam) were found to enhance proliferation and differentiation capacity of mesenchymal stem cells in vitro3. We recently conducted a systematic meta-analysis on potential drug effects on NSCs4. Results show that profound knowledge on those is scarce apart for fluoxetine, an antidepressant that increases NSC proliferation. However, preliminary evidence indicates such effects, and potential mechanistic pathways have been identified (Figure).

We now aim to thoroughly investigate drug influences on NSC by state-of-the-art cell culture experiments. Drugs often subscribed in the elderly to counter effects of normal ageing such as moderately enhanced blood pressure or mild dyslipidaemia, will be investigated.

Objectives:

(1) Identify drug influences on the proliferation and differentiation capacity of NSCs

(2) Quantify such influences under different drug concentrations

(3) To identify mechanisms underlying these influences

(4) To confirm these effects in vivo using a model of accelerated brain ageing

 Methods and approach: In step 1, human NSCs will be cultured and longitudinally monitored in vitro. We will investigate proliferation with or without the presence of drugs in physiological concentrations (serum concentration of a 75 kg patient regularly receiving standard doses). Appropriate positive (fluoxetine) and negative controls (cytotoxic cryoprotectant) will be used. Growth curves will be recorded and analysed.

In step 2, we will next investigate differentiation of NSCs into neurons, astro- and oligodendrocytes with or without drug presence. Speed and efficacy of differentiation into the respective linages will be investigated by phenotypical observation, immunohistochemistry and fluorescence microscopy. Experiments in steps 1 and 2 will be performed in in both “young” and “aged” NSC (very low and high passage number).

In step 3, we will identify the mechanisms by which the drugs influence stem cell behaviour based on the know effects and impact pathways of the drugs. Targeted blocking or stimulation of these pathways will confirm the proposed mechanisms.

In step 4, an in vivo experiment will be performed. Ageing healthy Wistar Kyoto plus spontaneously hypertensive rats, the latter exhibiting moderately enhanced blood pressure and accelerated brain ageing5, will be treated with the drug showing the largest in vitro effect. We will investigate effects of long-term treatment on NSC numbers, location as well as brain plasticity.

References:

  1. Exp Cell Res 253:733-736
  2. Cell Res 19:672-682
  3. Cell Biol Int 35:235-248
  4. Stem Cells Transl Med 8:1202-1211
  5. Acta Neuropathol Commun 2:169

BBSRC Strategic Research Priority: Understanding the Rules of Life: Neuroscience and behaviour: Stem Cells

      Techniques that will be undertaken during the project:

      • cell culture work, including neural stem cell proliferation and differentiation
      • immunohistochemistry and in depth cell characterisation
      • single cell analysis
      • molecular biology
      • ex vivo tissue analysis

      Contact: Professor Johannes Boltze, University of Warwick