Concise Review: Stem Cell Therapy for Stroke Patients: Are We There Yet?

Abstract

Four decades of preclinical research demonstrating survival, functional integration, and behavioral effects of transplanted stem cells in experimental stroke models have provided ample scientific basis for initiating limited clinical trials of stem cell therapy in stroke patients. Although safety of the grafted cells has been overwhelmingly documented, efficacy has not been forthcoming. Two recently concluded stroke clinical trials on mesenchymal stem cells (MSCs) highlight 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. Echoing the Stem Cell Therapeutics as an Emerging Paradigm for Stroke and Stroke Treatment Academic Industry Roundtable call for an NIH‐guided collaborative consortium of multiple laboratories in testing the safety and efficacy of stem cells and their derivatives, not just as stand‐alone but preferably in combination with approved thrombolytic or thrombectomy, may further increase the likelihood of successful fruition of translating stem cell therapy for stroke clinical application. The laboratory and clinical experience with MSC therapy for stroke may guide the future translational research on stem cell‐based regenerative medicine in neurological disorders. stem cells translational medicine 2019;8:983&988

Translating intracarotid artery transplantation of bone marrow-derived NCS-01 cells for ischemic stroke: Behavioral and histological readouts and mechanistic insights into stem cell therapy

“…Adult bone marrow‐derived stem cells, such as endothelial progenitor cells, hematopoietic, and mesenchymal stem cells (MSCs), have expedited the translation of lab‐to‐clinic stem cell therapy due to their logistical ease in isolation and amplification, and being relatively free from ethical concerns . MSCs have been explored as transplantable donor cells for many experimental models of neurological diseases, such as Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and stroke . Cell replacement was initially implicated in MSCs' therapeutic effects, yet with only modest graft survival despite robust functional outcomes, the currently accepted mechanism of action involves bystander repair processes primarily via stem cell‐secreted therapeutic factors .…”

“…For example, preclinical investigations employ approximately 4 million cells for IV administration for a 250 g stroke rat, corresponding to 840 million cells in a human of 75 kg, whereas clinical trials have employed doses well below those deemed optimal in preclinical animal models . This lack of translation of optimal laboratory parameters may explain these failed clinical efforts despite overwhelming experimental evidence . Recognizing these critical translational gaps, while acknowledging the long‐standing safety profile and the abundance of preclinical studies demonstrating neuroprotective effects, provides a solid rationale for testing the efficacy of an MSC line toward advancing stem cell therapy in stroke.…”

“…10,11 MSCs have been explored as transplantable donor cells for many experimental models of neurological diseases, 12,13 such as Parkinson's disease, [14][15][16] amyotrophic lateral sclerosis, [17][18][19] Alzheimer's disease, 20,21 and stroke. [22][23][24][25][26][27][28] Cell replacement was initially implicated in MSCs' therapeutic effects, yet with only modest graft survival despite robust functional outcomes, 29 the currently accepted mechanism of action involves bystander repair processes primarily via stem cell-secreted therapeutic factors. [30][31][32][33] This promising preclinical evidence, as well as solid safety record in treating hematological diseases, provides concrete grounds for clinical translation of MSC therapy in stroke.…”

An update on potentials and promises of T cell co‐signaling molecules in transplantation

“…Regarding these effects, exploiting the immunoregulatory properties of these nonclassical MHC molecules to induce local immuno- neurodegenerative diseases (Borlongan, 2019;R. Liu et al, 2012;Zarriello et al, 2018), stem cells modified to overexpress HLA-G or HLA-E might have great impact on the outcomes of upcoming studies.…”

“…Regarding the expression of HLA‐G and HLA‐E inhibitory receptors on a broad range of cells (Regis et al, ) and just a limited literature, the role of these molecules in the regulation of alloreactive immune responses needs to be further investigated. Regarding the promising outcomes of stem cell‐based therapies in neurodegenerative diseases (Borlongan, ; R. Liu et al, ; Zarriello et al, ), stem cells modified to overexpress HLA‐G or HLA‐E might have great impact on the outcomes of upcoming studies. The inflammatory nature of these diseases along with an urge for fair immunologic acceptance, provide the proportional logic for use of such stem cells in the case neurodegenerative conditions.…”