Stem Cell-Based Tissue Replacement After Stroke: Factual Necessity or Notorious Fiction?

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The increasing stroke incidence and the long-term, severe disability of survivors requiring complex nursing care over extended time periods cause an enormous social and economic burden to ageing societies. Unfortunately, all clinical trials on neuroprotectants have failed thus far.1 The only approved therapy is clot lysis (recombinant tissue-type plasminogen activator [r-tPA]), which is restricted to only 4.5 hours poststroke onset.2 Although r-tPA application is statistically justified, it can result in severe adverse events,3 complicating individual r-tPA treatment decisions. Thus, the current strategies in stroke management are focused on prevention by identification of risk factors4 and intensive rehabilitation in the chronic phase.5 However, stroke outcomes remain poor, causing a strong but unmet demand for alternative therapeutic approaches. The failure of the neuroprotective paradigm and limited eligibility for thrombolysis spawned an interest in stem cell–based neurorestoration,6 which is characterized by a wide therapeutic window and is highly convergent with rehabilitation. However, stem cell–based tissue replacement may be aggravated by pathophysiological and anatomic features, whereas the beneficial effects of (stem) cells may not necessarily result from cellular restoration. Here, we review the state of the art of cell-based stroke therapies and balance arguments supporting and challenging the concept of poststroke tissue restoration. Moreover, we discuss the respective therapeutic mechanisms related to tissue restoration versus indirect means of regenerative support including practical issues such as transplantation time windows, routes of cell administration, and potential detrimental effects. The replacement of lost brain tissue by transplanted cells has fired the imagination of researchers for decades. Studies on lesion-induced axonal sprouting of catecholamine neurons devised the fundamentals for brain-regenerating strategies. Then, the functional connections of transplanted monoamine neurons were demonstrated, whereas fetal nigral transplants were able to reverse parkinsonism in animal models and patients.7 These early proof-of-principle studies supported the …