The author of this open access review asks whether or not we can consider stem cell therapy to aid recovery from stroke to be a solved problem. Given that clinical trials are underway, is it just a matter of time and we can all agree that viable treatments exist? Unfortunately matters might not be that cut and dried, and recent clinical trials have failed for reasons that can be hypothesized to center around differences in the production of cells for transplantation. Nothing is ever straightforward in biology and medicine. Further, in the long term, why would we ever want medical technologies that only work after the damage is done? The more desirable goal in regenerative medicine is to prevent the deterioration that causes stroke and other traumatic damage to the brain, and thus never wind up in the position of needing greatly enhanced regenerative capacities.

In the late 1980s, researchers ushered one of the pioneering laboratory investigations in cell therapy for stroke, demonstrating the survival of rat fetal neocortical grafts in ischemic adult rat cortex. Subsequent studies showed that these grafted fetal cells integrated with the ischemic brain received afferent fibers and vascularization from the host intact tissue and responded to contralateral sensory stimulation with increased metabolic activity. Equally promising are the observations that stroke animals transplanted with fetal striatal cells into the ischemic striatum displayed some improvements in a simple cognitive task of passive avoidance, as well as in a more complex water maze learning test.

Over the next four decades of preclinical research, additional evidence of graft survival, migration, differentiation, and functional integration in the ischemic brain, modest anatomical reconstruction, and remodeling of brain circuitry, neurochemical, physiological, and behavioral recovery have been documented. Several mechanisms have also been postulated to mediate the therapeutic effects of cell transplants in stroke; although initially designed as a cell replacement for dead or ischemic cells, the current view puts robust bystander effects of the grafted cells to secrete therapeutic substances.

The recognition that stroke not only affects neurons but also other neural cell types, especially vascular cells, prompted the search for alternative regenerative processes that rescue in tandem neural and vascular cells, under the theme of attenuating the impaired neurovascular unit. Toward stimulating these non-neuronal repair processes, the stem cells' by-stander effects have been proposed, including the grafted cells' ability to secrete substances that promote neurogenesis, angiogenesis, vasculogenesis, anti-inflammation, among other therapeutic substances. Over the last five years, additional novel stem cell component-based mechanisms have been demonstrated to accompany stem cell therapy, such as the transfer of stem cell-derived mitochondria, exosomes, microvesicles, and microRNAs into the ischemic area.

Although safety of the grafted cells has been overwhelmingly documented, efficacy has not been forthcoming. This cell-based regenerative medicine remains designated as "experimental" in the clinic. Equally disappointing, two recently concluded clinical trials indicated stem cells are safe but not effective in stroke patients. These failed clinical trials may be due to a loss in translation of optimal laboratory stem cell transplantation protocols to clinical trial designs. The Good Manufacturing Practice (GMP)-manufactured stem cells are likely different from the laboratory-grade stem cells, in that the phenotype and biological properties originally designed to treat a specific disease in the laboratory may now have a different disease indication in the clinic. This highlights the importance of strict adherence to the basic science findings of optimal transplant regimen of cell dose, timing, and route of delivery in enhancing the functional outcomes of cell therapy.