Recent Advances in Mono- and Combined Stem Cell Therapies of Stroke in Animal Models and Humans

Abstract

Following the failure of acute neuroprotection therapies, major efforts are currently made worldwide to promote neurological recovery and brain plasticity in the subacute and post-acute phases of stroke. Currently, there is hope that stroke recovery might be promoted by cell-based therapies. The field of stem cell therapy for cerebral ischemia has made significant progress in the last five years. A variety of stem cells have been tested in animal models and humans including adipose stem cells, human umbilical cord blood-derived mesenchymal stem cells, human amnion epithelial cells, human placenta amniotic membrane-derived mesenchymal stem cells, adult human pluripotent-like olfactory stem cells, human bone marrow endothelial progenitor cells, electrically-stimulated human neuronal progenitor cells, or induced pluripotent stem cells (iPSCs) of human origin. Combination therapies in animal models include a mix of two or more therapeutic factors consisting of bone marrow stromal cells, exercise and thyroid hormones, endothelial progenitor cells overexpressing the chemokine CXCL12. Mechanisms underlying the beneficial effects of transplanted cells include the “bystander” effects, paracrine mechanisms, or extracellular vesicles-mediated restorative effects. Mitochondria transfer also appears to be a powerful strategy for regenerative processes. Studies in humans are currently limited to a small number of studies using autologous stem cells mainly aimed to assess tolerability and side-effects of human stem cells in the clinic.

Principles and requirements for stroke recovery science

“…the production of growth factors which promote survival and regeneration of preexisting brain cells. 19 , 20 Many attempts have been undertaken both in models of experimental stroke and in humans with different pharmacological and bioactive substances . All the various components of the regenerative processes have been used as targets for a pharmacological intervention.…”

Revisiting Stem Cell-Based Clinical Trials for Ischemic Stroke

“…BM-MSCs have been shown to cross the blood-brain barrier and improve functional recovery after acute ischemic stroke in animal models (Chen et al, 2001 ; Lee et al, 2016 ), likely due to a paracrine effect by secreting neurotrophic, mitogenic, and angiogenic factors, including VEGF, BDNF, nerve growth factor, basic fibroblast growth factor, and insulin-like growth factor 1 (Eckert et al, 2013 ; Shichinohe et al, 2015 ; Stonesifer et al, 2017 ). One hypothesized mode of delivery for these factors is via the secretion of membrane fragments (extracellular vesicles, EVs) from transplanted cells (Bang and Kim, 2019 ; Surugiu et al, 2019 ). Recent preclinical data in organoids suggest that EVs alone may be sufficient to significantly decrease injury in a hypoxia-starvation model of injury, opening the possibility for future early phase clinical trials of EV delivery for ischemic stroke (Zheng et al, 2020 ).…”

CD271+ stem cell treatment of patients with chronic stroke

“…Administration of MSCs in stroke patients via intravenous, intra-arterial, intracerebral and intrathecal routes was performed during the past two decades by many teams in many countries, mostly with cells from bone marrow, more recently from adipose tissue and umbilical cord blood ( 46 , 47 ).…”

“…A crucial aspect of stem cell treatment is the homing of stem cells in the brain after their administration; it was shown that Sdf-1 levels ( 46 ) elevated in subacute phase of stroke favors homing of stem cells in ischemic areas and a similar finding was published by a different team ( 54 ), however, we do not know if measuring the level of Sdf-1 has predictive value for successful administration of stem cells in specific patients and ASC homing remains an aspect in need of clarification ( 55 ).…”