Available treatments for stroke
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Thrombolysis medication, recombinant tissue plasminogen activators(rt-PA), such as alteplase, work by binding to the fibrin rich clots via the fibronectin finger-like domain and the Kringle 2 domain. Plasminogen is the inactive precursor of plasmin and is activated by rt-PA. The protease domain in rt-PA then cleaves the Arg561 - Val562 peptide bond in plasminogen to form plasmin. Plasmin is a serine protease and can cleave the haemostatic clot, consisting
Figure 5 Mechanism of t-PA action, (Genentech, 2014)
he medicines used for the treatment of ischemic stroke at the moment are alteplase, aspirin, heparin and other anticoagulants and mechanical thrombectomy.
of polymerized fibrin and platelets by proteolytic digestion. Therefore, rt-PA mediates recanalization of the congested vessels. (Figure 5) rt-PA is contraindicated in hemorrhagic stroke and older ischaemic stroke patients with mild or resolving symptoms and thrombophilia, as it increases the risk of intracranial bleeding.
Thrombectomy is the surgical removal of the blood clot, mechanically recanalising the obstructed vessels, used in patients unsuitable for rt-PA therapy or in combinations with it. It can be proximal and distal. (Figure 6) In proximal thrombectomy manual suction is performed by placing an aspiration catheter at the proximal surface of the thrombus. Then, manual aspiration is applied and the catheter is retrieved under constant negative pressure. Distal thrombectomy is more challenging technically. To deliver the device distally to the thrombus, a microcatheter is passed at the occlusion site. To avoid thromboembolic problems, a balloon guide catheter is placed in the cervical internal cerebral artery and aspiration during device retrieval is recommended for most devices. Several distal thrombectomy devices are in clinical practice, e.g. Merci, Catch, BALT. (Mordasini et al., 2012)
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Figure 6 Thrombectomy illustrated. A - Catheter aspiration thrombectomy B - Mechanical thrombectomy devices C - Proximal embolic protection devices D and E - Distal embolic protection devices (Mordasini P. et al., 2012) |
Stem cells
Stem cells can be distinguished from other cell types by the following characteristics:
They are unspecialized cells capable of self-renewal through mitosis, even after being inactive for a long time.
Certain physiological or experimental conditions can induce stem cells to become and function as organ or tissue specific cells.
Types of stem cells include:
Embryonic stem cells
Adult stem cells
Induced pluripotent stem cells
Embryonic stem cells
Embryonic stem cells (ESCs) are derived from the undifferentiated embryoblas of a blastocyst. Human embryos reach the blastocyst stage 4–5 days post fertilization. Removal of the embyoblast results in destruction of a blastocyst, which raises ethical concerns. ESCs are pluripotent, meaning they are able to differentiate into more than 220 cell types of the three primary germ layers: ectoderm, endoderm and mesoderm and have the ability to replicate indefinitely under defined conditions. This and ESC plasticity makes them potentially useful for research and regenerative medicine.
Adult stem cells
Also known as somatic stem cells (SSC) are multipotent, undifferentiated cells found at different sites throughout the body, which can multiply by mitosis to regenerate damaged tissues. Multipotency refers to adult stem cell ability to generate into distinct cell types; however research suggests that transdifferentiation capacity of some SSC can be improved by modification of the growth medium used when cultured in vitro producing induced pluripotent stem cells. (Yamanaka and Blau, 2010) Many different types of SSCs from different origins have been identified, including: umbilical cord stem cells, mesenchymal stem cells, neural stem cells, hematopoietic stem cells and limbal stem cells. As these cells can be harvested from the patient, without ethical concerns, many researchers have focused on SSC therapeutic potential for a variety of diseases. Yet, culturing SSCs up to the necessary numbers is still considered a challenge.
Induced pluripotent stem cells
Induced pluripotent stem cells (iPSCs) are specialised somatic cells, which have been genetically modified by injection of DNA or transcription factors to behave like ESC. iPSCs raise high hopes for future therapy, as they eliminate the risk of immune rejection by the patient, however, due to the novel nature of the technology and the not well understood process of reprogramming, unfortunately iPSC therapy is only theoretical at the moment. A way to improve iPSC safety needs to be found, as sometimes after genetic modification iPSCs have been shown to form tumours. (Liang et al., 2013)
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Figure 7 Pluripotent ESC types and multipotent adult stem cell and pathological disorders that might benefit from ESC and SSC therapies.
Abbreviations: BASCs, bronchioalveolar stem cells; bESCs, bulge epithelial stem cells; CESCs, corneal epithelial stem cells; CSCs, cardiac stem cells; eNCSCs, epidermal neural crest stem cells; ESCs, embryonic stem cells; EPC, endothelial progenitor cell; HOCs, hepatic oval cells; HSCs, hematopoetic stem cells; KSCs, keratinocyte stem cells; MSCs, mesenchymal stem cells; NSCs, neuronal stem cells; PSCs, pancreatic stem cells; RSCs, retinal stem cells; SKPs, skin-derived precursors. (Mimeault et al., 2007)