Comparative Characterization of Ischemia-Induced Brain Multipotent Stem Cells with Mesenchymal Stem Cells: Similarities and Differences

Abstract

Mesenchymal stem cells (MSCs) are multipotent stem cells localized to the perivascular regions of various organs, including bone marrow (BM). While MSC transplantation represents a promising stem cell-based therapy for ischemic stroke, increasing evidence indicates that exogenously administered MSCs rarely accumulate in the injured central nervous system (CNS). Therefore, compared with MSCs, regionally derived brain multipotent stem cells may be a superior source to elicit regeneration of the CNS following ischemic injury. We previously identified ischemia-induced multipotent stem cells (iSCs) as likely originating from brain pericytes/perivascular cells (PCs) within poststroke regions. However, detailed characteristics of iSCs and their comparison with MSCs remains to be investigated. In the present study, we compared iSCs with BM-derived MSCs, with a focus on the stemness and neuron-generating activity of each cell type. From our results, stem and undifferentiated cell markers, including c-myc and Klf4, were found to be expressed in iSCs and BM-MSCs. In addition, both cell types exhibited the ability to differentiate into mesoderm lineages, including as osteoblasts, adipocytes, and chondrocytes. However, compared with BM-MSCs, high expression of neural stem cell markers, including nestin and Sox2, were found in iSCs. In addition, iSCs, but not BM-MSCs, formed neurosphere-like cell clusters that differentiated into functional neurons. These results demonstrate that iSCs are likely multipotent stem cells with the ability to differentiate into not only mesoderm, but also neural, lineages. Collectively, our novel findings suggest that locally induced iSCs may contribute to CNS repair by producing neuronal cells following ischemic stroke.

Neural regeneration by regionally induced stem cells within post-stroke brains: Novel therapy perspectives for stroke patients

“…Using brain samples obtained from stroke patients who needed both decompressive craniectomy and partial lobectomy as a life-saving therapy for diffuse cerebral infarction, we attempted to isolate human iNSPCs/iSCs. We detected iNSPCs/iSCs within post-stroke areas of the human brains, consistent with those of mouse brains[21,24,41,90].…”

“…Comparing iNSPCs/iSCs with other types of multipotent stem cells such as bone-marrow-derived MSCs, iNSPCs/iSCs differentiate into mesenchymal lineages, including osteoblasts and adipocytes as well as MSCs. Using multi-electrode arrays[89], we recently reported that iNSPCs/iSCs, but not MSCs, have the potential to differentiate into electrophysiologic-functional neurons[90]. On the basis of their developmental origin in multiple organs, the majority of non-CNS pericytes originate from the mesoderm.…”

How Long Are Reperfusion Therapies Beneficial for Patients after Stroke Onset? Lessons from Lethal Ischemia Following Early Reperfusion in a Mouse Model of Stroke

“…Although it remains unclear whether brain pericytes are identical to brain MSCs [ 94 ], it was reported that the traits of MSCs differ among organs [ 95 ]. In support of this finding, we recently showed that compared with bone marrow-derived MSCs, iSCs, which likely originated from brain pericytes, predominately had neural rather than mesenchymal lineages, although they possessed several common pericytic (PDGFRβ, NG2, and αSMA) and mesenchymal markers (CD29, CD44, CD73, CD105, CD106, and CD166) [ 96 , 97 , 98 , 99 ]. We also demonstrated that iSCs were present in post-stroke human brain [ 99 ] and that iSCs obtained from mouse [ 98 ] and human brains [ 96 , 97 ] differentiate into electrophysiologically functional neurons.…”

“…In support of this finding, we recently showed that compared with bone marrow-derived MSCs, iSCs, which likely originated from brain pericytes, predominately had neural rather than mesenchymal lineages, although they possessed several common pericytic (PDGFRβ, NG2, and αSMA) and mesenchymal markers (CD29, CD44, CD73, CD105, CD106, and CD166) [ 96 , 97 , 98 , 99 ]. We also demonstrated that iSCs were present in post-stroke human brain [ 99 ] and that iSCs obtained from mouse [ 98 ] and human brains [ 96 , 97 ] differentiate into electrophysiologically functional neurons. These results indicate that factors regulating the fate of endogenous iSCs (e.g., factors promoting cell proliferation of iSCs or factors inhibiting cell death of iSCs) can facilitate neural repair and may be clinically useful in treating patients with stroke [ 100 ].…”

<p>Efficacy and Safety of Umbilical Cord Mesenchymal Stem Cell Therapy for Rheumatoid Arthritis Patients: A Prospective Phase I/II Study</p>

“…25 In addition, when MSCs differentiate into other types of cells, it still retains its immunomodulatory effect; 26 Fifthly, MSCs have a chemotaxis effect, which can prevent the release of inflammatory mediators, reduce the inflammatory reaction and tissue damage, and disease progression. 27,28 In this study, after the treatment of UC-MSC for RA patients, personalized low dose of DMARDs therapy was maintained for a long time. The serological indexes of the patients were stable for a long time, reaching the low activity level of RA, which was consistent with the improved clinical symptoms.…”