scholarly journals Clot-Derived Contaminants in Transplanted Bone Marrow Mononuclear Cells Impair the Therapeutic Effect in Stroke

Stroke ◽  
2019 ◽  
Vol 50 (10) ◽  
pp. 2883-2891 ◽  
Author(s):  
Yuka Okinaka ◽  
Akie Kikuchi-Taura ◽  
Yukiko Takeuchi ◽  
Yuko Ogawa ◽  
Johannes Boltze ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Mononuclear Cells ◽  
Blood Clot ◽  
Experimental Stroke ◽  
Bone Marrow Mononuclear Cell ◽  
Therapeutic Effects ◽  
Beneficial Effects ◽  
Preclinical And Clinical Studies ◽  
Possible Cause

Background and Purpose— The beneficial effects of bone marrow mononuclear cell (BM-MNC) transplantation in preclinical experimental stroke have been reliably demonstrated. However, only overall modest effects in clinical trials were observed. We have investigated and reported a cause of the discrepancy between the preclinical and clinical studies. Methods— To investigate the possible cause of low efficacy of BM-MNC transplantation in experimental stroke, we have focused on blood clot formation, which is not uncommon in human bone marrow aspirates. To evaluate the effects of clot-derived contaminants in transplanted BM-MNC on stroke outcome, a murine stroke model was used. Results— We show that BM-MNC separated by an automatic cell isolator (Sepax2), which does not have the ability to remove clots, did not attenuate brain atrophy after stroke. In contrast, manually isolated, clot-free BM-MNC exerted therapeutic effects. Clot-derived contaminants were also transplanted intravenously to poststroke mice. We found that the transplanted contaminants were trapped at the peristroke area, which were associated with microglial/macrophage activation. Conclusions— Clot-derived contaminants in transplanted BM-MNC nullify therapeutic effects in experimental stroke. This may explain neutral results in clinical trials, especially in those using automated stem cell separators that lack the ability to remove clot-derived contaminants. Visual Overview— An online visual overview is available for this article.

scholarly journals Cell Therapies under Clinical Trials and Polarized Cell Therapies in Pre-Clinical Studies to Treat Ischemic Stroke and Neurological Diseases: A Literature Review

2020 ◽  
Vol 21 (17) ◽  
pp. 6194 ◽  
Author(s):  
Masahiro Hatakeyama ◽  
Itaru Ninomiya ◽  
Yutaka Otsu ◽  
Kaoru Omae ◽  
Yasuko Kimura ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Ischemic Stroke ◽  
Clinical Studies ◽  
Mononuclear Cells ◽  
Neurological Diseases ◽  
Functional Independence ◽  
Therapeutic Effects ◽  
Cell Therapies ◽  
Neuronal Stem Cells

Stroke remains a major cause of serious disability because the brain has a limited capacity to regenerate. In the last two decades, therapies for stroke have dramatically changed. However, half of the patients cannot achieve functional independence after treatment. Presently, cell-based therapies are being investigated to improve functional outcomes. This review aims to describe conventional cell therapies under clinical trial and outline the novel concept of polarized cell therapies based on protective cell phenotypes, which are currently in pre-clinical studies, to facilitate functional recovery after post-reperfusion treatment in patients with ischemic stroke. In particular, non-neuronal stem cells, such as bone marrow-derived mesenchymal stem/stromal cells and mononuclear cells, confer no risk of tumorigenesis and are safe because they do not induce rejection and allergy; they also pose no ethical issues. Therefore, recent studies have focused on them as a cell source for cell therapies. Some clinical trials have shown beneficial therapeutic effects of bone marrow-derived cells in this regard, whereas others have shown no such effects. Therefore, more clinical trials must be performed to reach a conclusion. Polarized microglia or peripheral blood mononuclear cells might provide promising therapeutic strategies after stroke because they have pleiotropic effects. In traumatic injuries and neurodegenerative diseases, astrocytes, neutrophils, and T cells were polarized to the protective phenotype in pre-clinical studies. As such, they might be useful therapeutic targets. Polarized cell therapies are gaining attention in the treatment of stroke and neurological diseases.

scholarly journals Clinical Trials of Stem Cell Therapy for Cerebral Ischemic Stroke

2020 ◽  
Vol 21 (19) ◽  
pp. 7380 ◽  
Author(s):  
Masahito Kawabori ◽  
Hideo Shichinohe ◽  
Satoshi Kuroda ◽  
Kiyohiro Houkin
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Clinical Trials ◽  
Stem Cell ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Therapeutic Effects ◽  
Stroke Patients

Despite recent developments in innovative treatment strategies, stroke remains one of the leading causes of death and disability worldwide. Stem cell therapy is currently attracting much attention due to its potential for exerting significant therapeutic effects on stroke patients. Various types of cells, including bone marrow mononuclear cells, bone marrow/adipose-derived stem/stromal cells, umbilical cord blood cells, neural stem cells, and olfactory ensheathing cells have enhanced neurological outcomes in animal stroke models. These stem cells have also been tested via clinical trials involving stroke patients. In this article, the authors review potential molecular mechanisms underlying neural recovery associated with stem cell treatment, as well as recent advances in stem cell therapy, with particular reference to clinical trials and future prospects for such therapy in treating stroke.

From mesenchymal stem cells and stromal cells - from bench to bedside

2019 ◽  
Vol 1 (1) ◽  
pp. 36-39
Author(s):  
Bernd Giebel ◽  
Verena Börger ◽  
Mario Gimona ◽  
Eva Rohde
Keyword(s):  
Stem Cells ◽  
Clinical Trials ◽  
Mesenchymal Stem Cells ◽  
Stromal Cells ◽  
Therapeutic Agent ◽  
Therapeutic Potential ◽  
Therapeutic Effects ◽  
Cell Replacement ◽  
Beneficial Effects ◽  
Promising Tool

Human mesenchymal stem/stromal cells (MSCs) represent a promising tool in regenerative medicine. Until now, almost one thousand NIH-registered clinical trials investigated their immunomodulatory and pro-regenerative therapeutic potential in various diseases. Despite controversial reports regarding the efficacy of MSC-treatments, MSCs appear to exert their beneficial effects in a paracrine manner rather than by cell replacement. In this context, extracellular vesicles (EVs), such as exosomes and microvesicles, seem to induce the MSCs’ therapeutic effects. Here, we briefly illustrate the potential of MSC-EVs as therapeutic agent of the future.

Therapeutic angiogenesis by autologous adipose-derived regenerative cells: comparison with bone marrow mononuclear cells

2014 ◽  
Vol 307 (6) ◽  
pp. H869-H879 ◽  
Author(s):  
Changning Hao ◽  
Satoshi Shintani ◽  
Yuuki Shimizu ◽  
Kazuhisa Kondo ◽  
Masakazu Ishii ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mononuclear Cells ◽  
Umbilical Vein ◽  
Rabbit Model ◽  
Bone Marrow Mononuclear Cell ◽  
M2 Macrophages ◽  
Hindlimb Ischemia ◽  
Macrophages Polarization ◽  
Ischemic Muscle

Transplantation of adipose-derived regenerative cell (ADRC) enhances ischemia-induced angiogenesis, but the underlying mechanism remains unknown. Here, we compared the efficacy between ADRC and bone marrow mononuclear cell (BM-MNC) transplantation in rabbits model of hindlimb ischemia and examined the possible roles of alternative phenotypic macrophages polarization in ADRC-mediated angiogenesis using mice model of hindlimb ischemia. ADRCs and BM-MNCs were isolated from New Zealand White rabbits and C57BL/6J mice. In rabbit studies, our data showed that ADRCs could incorporate into the endothelial vasculature in vitro and in vivo. Both ADRC-conditioned media (CM) and BM-MNC-CM enhanced the migratory ability and interrupted the process of apoptosis in human umbilical vein endothelial cells. Four weeks after cell transplantation, augmentation of postnatal neovascularization was observed in the ischemic muscle injected with either ADRCs or BM-MNCs. In mice studies, we presented that ADRCs polarized into the IL-10-releasing M2 macrophages through PGE2-EP2/4 axis and suppressed the expressions of TNF-α and IL-6 in the ischemic muscle. Gene expressions of several angiogenic cytokines were amplified in the macrophages cultured in ADRC-CM rather than BM-MNC-CM. Blockade of IL-10 using neutralizing MAb attenuated the ADRC-mediated angiogenesis and caused muscle apoptosis in vivo. In conclusion, ADRC transplantation harvested similar effect of neovascularization augmentation compared with BM-MNC in experimental rabbit model of hindlimb ischemia; ADRC displayed a unique immunoregulatory manner of accelerating IL-10-releasing M2 macrophages polarization through the PGE2-EP2/4 axis.

scholarly journals Comparable Effects of the Androgen Derivatives Danazol, Oxymetholone and Nandrolone on Telomerase Activity in Human Primary Hematopoietic Cells from Patients with Dyskeratosis Congenita

2020 ◽  
Vol 21 (19) ◽  
pp. 7196
Author(s):  
Margherita Vieri ◽  
Martin Kirschner ◽  
Mareike Tometten ◽  
Anne Abels ◽  
Benjamin Rolles ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mononuclear Cells ◽  
Therapeutic Option ◽  
Telomerase Activity ◽  
Dyskeratosis Congenita ◽  
Telomere Maintenance ◽  
Inherited Disease ◽  
Beneficial Effects ◽  
Tert Expression

Dyskeratosis congenita (DKC) is a rare inherited disease of impaired telomere maintenance that progressively leads to multi-organ failure, including the bone marrow. By enhancing telomerase activity, androgen derivatives (ADs) are a potential therapeutic option able to re-elongate previously shortened telomeres. Danazol, oxymetholone, and nandrolone are ADs most frequently used to treat DKC. However, no direct in vitro analyses comparing the efficacy of these ADs have been conducted so far. We therefore treated mononuclear cells derived from peripheral blood and bone marrow of four patients with mutations in telomerase reverse transcriptase (TERT, n = 1),in the telomerase RNA component (TERC, n = 2) and in dyskerin pseudouridine synthase 1 (DKC1, n = 1) and found no substantial differences in the activity of these three agents in patients with TERC/TERT mutations. All AD studied produced comparable improvements of proliferation rates as well as degrees of telomere elongation. Increased TERT expression levels were shown with danazol and oxymetholone. The beneficial effects of all ADs on proliferation of bone marrow progenitors could be reversed by tamoxifen, an estrogen antagonist abolishing estrogen receptor-mediated TERT expression, thereby underscoring the involvement of TERT in AD mechanism of action. In conclusion, no significant differences in the ability to functionally enhance telomerase activity could be observed for the three AD studied in vitro. Physicians therefore might choose treatment based on patients’ individual co-morbidities, e.g., pre-existing liver disease and expected side-effects.

Bone marrow mononuclear cell transplantation had beneficial effects on doxorubicin-induced cardiomyopathy

2004 ◽  
Vol 23 (4) ◽  
pp. 436-445 ◽  
Author(s):  
Michiko Ishida ◽  
Shinji Tomita ◽  
Takeshi Nakatani ◽  
Shinya Fukuhara ◽  
Masaki Hamamoto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Transplantation ◽  
Mononuclear Cell ◽  
Bone Marrow Mononuclear Cell ◽  
Beneficial Effects
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