Evidence for High Translational Potential of Mesenchymal Stromal Cell Therapy to Improve Recovery from Ischemic Stroke

Abstract

Although ischemic stroke is a major cause of morbidity and mortality, current therapies benefit only a small proportion of patients. Transplantation of mesenchymal stromal cells (MSC, also known as mesenchymal stem cells or multipotent stromal cells) has attracted attention as a regenerative therapy for numerous diseases, including stroke. Mesenchymal stromal cells may aid in reducing the long-term impact of stroke via multiple mechanisms that include induction of angiogenesis, promotion of neurogenesis, prevention of apoptosis, and immunomodulation. In this review, we discuss the clinical rationale of MSC for stroke therapy in the context of their emerging utility in other diseases, and their recent clinical approval for treatment of graft-versus-host disease. An analysis of preclinical studies examining the effects of MSC therapy after ischemic stroke indicates near-universal agreement that MSC have significant favorable effect on stroke recovery, across a range of doses and treatment time windows. These results are interpreted in the context of completed and ongoing human clinical trials, which provide support for MSC as a safe and potentially efficacious therapy for stroke recovery in humans. Finally, we consider principles of brain repair and manufacturing considerations that will be useful for effective translation of MSC from the bench to the bedside for stroke recovery.

The long-term fate of mesenchymal stem cells labeled with magnetic resonance imaging-visible polymersomes in cerebral ischemia

“…MSCs might exert their therapeutic effect via paracrine factors rather than in vivo transdifferentiation into neuronal and/or glial phenotypes. 18,19 Maintaining long-term survival, accurate homing, and migration of stem cells must first be accomplished before clinical applications in humans. 27 MRI has been the most widely investigated imaging modality for in vivo tracking of the biodistribution and migration of stem cells in a stroke.…”

“…A number of divergent mechanisms have been proposed, such as differentiation into cell types relevant to repair and cell replacement, modulation of the immune system, secretion of neuroprotective and neurotrophic factors, and promotion of angiogenesis and neurogenesis. 18,19 In our study, only a few viable MSCs were differentiated into astrocytes, but not into neurons. Both labeled and unlabeled GFP-MSCs offered a therapeutic benefit on stroke.…”

“…18,19 Initially, it was assumed that transdifferentiation of MSCs into neuronal and glial cells to replace damaged cells might play a pivotal role in stroke recovery. 18,20 Nonetheless, growing evidence suggested that the enhanced function recovery of MSCs might not be mainly associated with the transdifferentiation of MSCs. 20 Since MSCs can secrete a vast array of cytokines, chemokines, angiogenic factors, and growth factors, paracrine action might play an essential role in brain regeneration in MSCs therapy.…”

The 3 Rs of Stroke Biology: Radial, Relayed, and Regenerative

“…Other molecular pathways for axonal sprouting, either induced in peri-infarct neurons or contralateral neurons [98], indicate promising targets for neural repair such as ephrin-A5, GDF10, and the use of the small molecule inosine [36,69,98,113]. Cell therapies appear to stimulate local axonal sprouting by tissue immunohistochemical staining [117][118][119], and in some cases by more detailed direct demonstration of axonal connections [120]. These also represent a candidate neural repair approach.…”

Evaluation of parametric response mapping to assess therapeutic response to human mesenchymal stem cells after experimental stroke

“…To this end, there is a strong interest in the potential of cell transplantation. 2,3 Among the cell populations currently available, human mesenchymal stem cells (hMSCs), derived from bone marrow, seem to have definite therapeutic potential due to their low immunogenicity under either autologous or allogeneic conditions, [3][4][5] although potential complications including cell clotting and cell-induced microembolism might impair their therapeutic safety and efficacy. 6 Their responses to the particular pathological microenvironments of cerebral ischemia make hMSCs exert multiple therapeutic effects at various sites and times within the stroke lesion by preventing neural cell death and improving neurological function.…”