Concise Review: Increasing the Validity of Cerebrovascular Disease Models and Experimental Methods for Translational Stem Cell Research

Abstract

Interspecies differences, anatomical and physiological aspects, as wells as simplified study designs contribute to an overestimation of treatment effects and limit the transferability of experimental results into clinical applications. Confounders of cell therapies for cerebrovascular disorders (CVD) include common CVD comorbidities, frequent medications potentially affecting endogenous and transplanted stem cells, as well as age-and immune-system-related effects. All those can contribute to a substantial modeling bias, ultimately limiting the prospective quality of preclinical research programs regarding the clinical value of a particular cell therapy. In this review, we discuss the nature and impact of most relevant confounders. We provide suggestions on how they can be considered to enhance the validity of CVD models in stem cell research. Acknowledging substantial and sometimes surprising effects of housing conditions, chronobiology, and intersex differences will further augment the translational value of animal models. We finally discuss options for the implementation of high-quality functional and imaging readout protocols. Altogether, this might help to gain a more holistic picture about the therapeutic impact of a particular cell therapy for CVD, but also on potential side and off-site effects of the intervention. STEM CELLS 2017;35:1141-1153 SIGNIFICANCE STATEMENTThis review summarizes most important aspects that may affect stem cell and cell therapy impact in cerebrovascular disease research. We discuss relevant mechanisms potentially impacting stem cell efficacy, safety, as well as relevant options to increase the predictive value of translational research programs. Importantly, the review also covers so far underrepresented areas such as chronobiology, comorbidities, polypharmacology (effects of drugs on stem cell efficacy and behavior), as well as potential species-specific aspects of stem cell performance.

Functional Outcome of Human Adipose Stem Cell Injections in Rat Anal Sphincter Acute Injury Model

“…Xenotransplantation has been used before to study development, physiology, and pathophysiology of human tissues in animal models, for example, enteric nervous system [48] and rodent models have been tested in treatment of stroke [49] and myocardial infarct [50]. However, there are differences in human and animal physiology that have to be kept in mind when interpreting the results [51].…”

Stem cell therapy for stroke: lessons learned from recent successful randomized trials of interventional therapy for stroke

“…Possible patient factors that may affect their response to stem cell therapy include gender and age of donor/recipient [32], comorbidity (such as diabetes) [33][34][35], and stroke medication (such as aspirin and statins) [36] which may affect endogenous and transplanted stem cells. Severity of brain injury may also be important since patients with extensive damage to the periventricular region were observed to have a lesser degree of improvement after stem cell therapy [4].…”

Cell Therapy in Stroke—Cautious Steps Towards a Clinical Treatment

“…The experimental literature gives the impression that cell therapy should be effective in improving behavioral recovery after stroke (13,16). However, the critical evaluation of experimental research has been limited (20). Experimental cell therapy research suffers from many technical and methodological limitations as described for acute neuroprotection (21,22), deficiencies which were initially highlighted in the Stroke Therapy Academic-Industry Roundtable (STAIR) meetings.…”