Abstract 241: Direct Injection of Bone Marrow Mononuclear Cells Reversed Experimental Diabetic Neuropathy by Augmenting Neovascularization and Providing Angio-neurotrophic Cytokines

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Hyongbum Kim ◽  
Yong Jin Choi ◽  
Jong-seon Park ◽  
Masaaki Ii ◽  
Marcy Silver ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Diabetic Neuropathy ◽  
Neurotrophic Factors ◽  
Mononuclear Cells ◽  
Motor Nerve ◽  
Therapeutic Option ◽  
Direct Injection ◽  
Saline Group ◽  
Vasa Nervorum ◽  
Sciatic Nerves

Background: Bone marrow (BM)-derived mononuclear cells (MNCs) have been shown to effectively treat ischemic cardiovascular diseases. Recent evidence suggested that diabetic neuropathy (DN) is causally related to impaired angio-vasculogenesis in vasa nervorum and deficiency of angiogenic and neurotrophic factors. Accordingly, we sought to investigate whether DN can be ameliorated by local injection of BM-derived MNCs. Methods and Results: A severe peripheral neuropathy, characterized by significant slowing of motor nerve conduction velocities (MCV) developed 12 wks after the induction of diabetes with streptozotocin in Fisher rats (vs normal rats; 46.6±2.6 vs 32.0±2.5 m/s, P < 0.05). These rats were randomly assigned to MNC or saline injection groups (n = 9, each group) and received either 5x106 MNCs or saline intramuscularly around the sciatic nerves. In the MNC group, MCV were significantly improved within 4 wks after treatment (MNC vs Saline, 41.9±3.2 vs 32.7±2.8 m/s, P < 0.01). Microvascular circulation of sciatic nerve, measured by laser Doppler perfusion imaging was markedly increased only in the MNC group. Capillary density at 4 wks was significantly higher in the MNC group than in the saline group (68±5.9 vs 37±4.4 /cross section, P < 0.01). Robust engraftment of MNCs were observed in sciatic nerves, which sustained over 4 wks. A fraction of engrafted MNCs expressed endothelial markers suggestive of transdifferentiation into endothelial cells in the vasa nervorum. Intriguingly, a large number of the engrafted MNCs are following the course of vasa nervorum in close proximity. Real-time RT-PCR on sciatic nerves revealed that the expression of angio-neurotrophic factors were significantly increased in the MNC group compared to the saline group: VEGF (2.1 fold), FGF-2 (2.4), eNOS (18.1), Brain-derived neurotrophic factor (35.1), IGF-1 (25.5) (all P < 0.05). The protein levels were well correlated with mRNA expression levels. Conclusion: Local transplantation of BM-derived MNCs could improve experimental DN by augmenting neovascularization and increasing angiogenic and neurotrophic factors in peripheral nerves. These findings suggest that BM-MNC transplantation may represent a novel therapeutic option for treating DN.

Transplantation of human mobilized mononuclear cells improved diabetic neuropathy

2018 ◽  
Vol 239 (3) ◽  
pp. 277-287
Author(s):  
Se Hee Min ◽  
Jung Hee Kim ◽  
Yu Mi Kang ◽  
Seung Hak Lee ◽  
Byung-Mo Oh ◽  
...  
Keyword(s):  
Stem Cells ◽  
Diabetic Neuropathy ◽  
Mononuclear Cells ◽  
Related Factor ◽  
Paracrine Effects ◽  
Muscle Perfusion ◽  
Hind Limbs ◽  
Compound Muscle Action Potentials ◽  
Sciatic Nerves

Rodent stem cells demonstrated regenerative effects in diabetic neuropathy via improvement in nerve perfusion. As a pre-clinical step, we explored if human mobilized mononuclear cells (hMNC) would have the same effects in rats. hMNC were injected into Rt. hind-limb muscles of streptozotocin-induced diabetic nude rats, and the grafts were monitored using with MRI. After 4 weeks, the effects were compared with those in the vehicle-injected Lt. hind limbs. Nerve conduction, muscle perfusion and gene expression of sciatic nerves were assessed. Induction of diabetes decreased nerve function and expression of Mpz and Met in the sciatic nerves, which are related with myelination. hMNC injection significantly improved the amplitude of compound muscle action potentials along with muscle perfusion and sciatic nerve Mpz expression. On MRI, hypointense signals were observed for 4 weeks at the graft site, but their correlation with the presence of hMNC was detectable for only 1 week. To evaluate paracrine effects of hMNC, IMS32 cells were tested with hepatocyte growth factor (HGF), which had been reported as a myelination-related factor from stem cells. We could observe that HGF enhanced Mpz expression in the IMS32 cells. Because hMNC secreted HGF, IMS32 cells were co-cultured with hMNC, and the expression of Mpz increased along with morphologic maturation. The hMNC-induced Mpz expression was abrogated by treatment of anti-HGF. These results suggest that hMNC could improve diabetic neuropathy, possibly through enhancement of myelination as well as perfusion. According to in vitro studies, HGF was involved in the hMNC-induced myelination activity, at least in part.

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.

scholarly journals Transplantation of Bone Marrow-Derived Mononuclear Cells Improves Mechanical Hyperalgesia, Cold Allodynia and Nerve Function in Diabetic Neuropathy

PLoS ONE ◽  
2011 ◽  
Vol 6 (11) ◽  
pp. e27458 ◽  
Author(s):  
Keiko Naruse ◽  
Jun Sato ◽  
Megumi Funakubo ◽  
Masaki Hata ◽  
Nobuhisa Nakamura ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Diabetic Neuropathy ◽  
Mononuclear Cells ◽  
Mechanical Hyperalgesia ◽  
Nerve Function ◽  
Cold Allodynia

scholarly journals Intravenous Bone Marrow Mononuclear Cells Transplantation Improves the Effect of Training in Chronic Stroke Mice

2020 ◽  
Vol 7 ◽  
Author(s):  
Yuko Ogawa ◽  
Yuka Okinaka ◽  
Yukiko Takeuchi ◽  
Orie Saino ◽  
Akie Kikuchi-Taura ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Therapy ◽  
Mononuclear Cells ◽  
Therapeutic Option ◽  
Artery Occlusion ◽  
Chronic Stroke ◽  
Therapeutic Effects ◽  
Bone Marrow Mononuclear Cells ◽  
Stroke Treatment ◽  
Cerebral Artery Occlusion

There is no effective treatment for chronic stroke if the acute or subacute phase is missed. Rehabilitation alone cannot easily achieve a dramatic recovery in function. In contrast to significant therapeutic effects of bone marrow mononuclear cells (BM-MNC) transplantation for acute stroke, mild and non-significant effects have been shown for chronic stroke. In this study, we have evaluated the effect of a combination of BM-MNC transplantation and neurological function training in chronic stroke. The effect of BM-MNC on neurological functional was tested four weeks after permanent middle cerebral artery occlusion (MCAO) insult in mice. BM-MNC (1 × 105cells in 100 μl PBS) were injected into the vein of MCAO model mice, followed by behavioral tests as functional evaluations. Interestingly, there was a significant therapeutic effect of BM-MNC only when repeated training was performed. This suggested that cell therapy alone was not sufficient for chronic stroke treatment; however, training with cell therapy was effective. The combination of these differently targeted therapies provided a significant benefit in the chronic stroke mouse model. Therefore, targeted cell therapy via BM-MNC transplantation with appropriate training presents a promising novel therapeutic option for patients in the chronic stroke period.

scholarly journals Bone Marrow Mononuclear Cells Have Neurovascular Tropism and Improve Diabetic Neuropathy

Stem Cells ◽  
2009 ◽  
Vol 27 (7) ◽  
pp. 1686-1696 ◽  
Author(s):  
Hyongbum Kim ◽  
Jong-seon Park ◽  
Yong Jin Choi ◽  
Mee-Ohk Kim ◽  
Yang Hoon Huh ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Diabetic Neuropathy ◽  
Mononuclear Cells ◽  
Bone Marrow Mononuclear Cells

scholarly journals The combination of G-CSF and AMD3100 mobilizes bone marrow-derived stem cells to protect against cisplatin-induced acute kidney injury in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhi Chen ◽  
Xiang Ren ◽  
Ruimin Ren ◽  
Yonghong Wang ◽  
Jiwen Shang
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Kidney Injury ◽  
Renal Function ◽  
Tissue Injury ◽  
Therapeutic Option ◽  
Kidney Injury ◽  
Saline Group ◽  
Inflammatory Factors ◽  
Tissue Samples

Abstract Background Several studies have confirmed that mobilizing bone marrow-derived stem cells (BMSCs) ameliorates renal function loss following cisplatin-induced acute kidney injury (AKI). The aim of this study was to explore whether the combination of granulocyte-colony stimulating factor (G-CSF) and plerixafor (AMD3100) exerts beneficial effects on renal function recovery in a model of cisplatin-induced nephrotoxicity. Methods C57BL/6J mice received intraperitoneal injections of G-CSF (200 μg/kg/day) for 5 consecutive days. On the day of the last injection, the mice received a single subcutaneous dose of AMD3100 (5 mg/kg) 1 h before cisplatin 20 mg/kg injection. Ninety-six hours after cisplatin injection, the mice were euthanized, and blood and tissue samples were collected to assess renal function and tissue damage. Cell mobilization was assessed by flow cytometry (FCM). Results Mice pretreated with G-CSF/AMD3100 exhibited longer survival and lower serum creatinine and blood urea nitrogen (BUN) levels than mice treated with only G-CSF or saline. Combinatorial G-CSF/AMD3100 treatment attenuated tissue injury and cell death, enhanced cell regeneration, and mobilized a higher number of stem cells in the peripheral blood than G-CSF or saline treatment. Furthermore, the mRNA expression of proinflammatory factors was lower, whereas that of anti-inflammatory factors was higher, in the G-CSF/AMD3100 group than in the G-CSF or saline group (all P < 0.05). Conclusions These results suggest that combinatorial G-CSF/AMD3100 therapy mobilizes BMSCs to accelerate improvements in renal functions and prevent cisplatin-induced renal tubular injury. This combinatorial therapy may represent a new therapeutic option for the treatment of AKI and should be further investigated in the future.

scholarly journals Morphology and morphometry of feline bone marrow-derived mesenchymal stem cells in culture

2014 ◽  
Vol 34 (11) ◽  
pp. 1127-1134 ◽  
Author(s):  
Bruno B. Maciel ◽  
Carmen L.K. Rebelatto ◽  
Paulo R.S. Brofman ◽  
Harald F.V. Brito ◽  
Lia F.L. Patricio ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Mononuclear Cells ◽  
Average Length ◽  
Therapeutic Option ◽  
Future Application ◽  
Morphometric Study ◽  
Morphometric Characteristics ◽  
Differentiation Potential

Mesenchymal stem cells (MSC) are increasingly being proposed as a therapeutic option for treatment of a variety of different diseases in human and veterinary medicine. Stem cells have been isolated from feline bone marrow, however, very few data exist about the morphology of these cells and no data were found about the morphometry of feline bone marrow-derived MSCs (BM-MSCs). The objectives of this study were the isolation, growth evaluation, differentiation potential and characterization of feline BM-MSCs by their morphological and morphometric characteristics. in vitro differentiation assays were conducted to confirm the multipotency of feline MSC, as assessed by their ability to differentiate into three cell lineages (osteoblasts, chondrocytes, and adipocytes). To evaluate morphological and morphometric characteristics the cells are maintained in culture. Cells were observed with light microscope, with association of dyes, and they were measured at 24, 48, 72 and 120h of culture (P1 and P3). The non-parametric ANOVA test for independent samples was performed and the means were compared by Tukey's test. On average, the number of mononuclear cells obtained was 12.29 (±6.05x10(6)) cells/mL of bone marrow. Morphologically, BM-MSCs were long and fusiforms, and squamous with abundant cytoplasm. In the morphometric study of the cells, it was observed a significant increase in average length of cells during the first passage. The cell lengths were 106.97±38.16µm and 177.91±71.61µm, respectively, at first and third passages (24 h). The cell widths were 30.79±16.75 µm and 40.18±20.46µm, respectively, at first and third passages (24 h).The nucleus length of the feline BM-MSCs at P1 increased from 16.28µm (24h) to 21.29µm (120h). However, at P3, the nucleus length was 26.35µm (24h) and 25.22µm (120h). This information could be important for future application and use of feline BM-MSCs.

scholarly journals Comprehensive characterization of central BCL-2 family members in aberrant eosinophils and their impact on therapeutic strategies

2021 ◽  
Author(s):  
Timo O. Odinius ◽  
Lars Buschhorn ◽  
Celina Wagner ◽  
Richard T. Hauch ◽  
Veronika Dill ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Kinase Inhibitors ◽  
Mononuclear Cells ◽  
Therapeutic Option ◽  
Treatment Options ◽  
Hypereosinophilic Syndrome ◽  
Myeloproliferative Neoplasm ◽  
Eosinophilic Granulomatosis With Polyangiitis ◽  
Chronic Eosinophilic Leukemia ◽  
Eosinophil Granulocytes

Abstract Purpose Hypereosinophilia represents a heterogenous group of severe medical conditions characterized by elevated numbers of eosinophil granulocytes in peripheral blood, bone marrow or tissue. Treatment options for hypereosinophilia remain limited despite recent approaches including IL-5-targeted monoclonal antibodies and tyrosine kinase inhibitors. Methods To understand aberrant survival patterns and options for pharmacologic intervention, we characterized BCL-2-regulated apoptosis signaling by testing for BCL-2 family expression levels as well as pharmacologic inhibition using primary patient samples from diverse subtypes of hypereosinophilia (hypereosinophilic syndrome n = 18, chronic eosinophilic leukemia not otherwise specified n = 9, lymphocyte-variant hypereosinophilia n = 2, myeloproliferative neoplasm with eosinophilia n = 2, eosinophilic granulomatosis with polyangiitis n = 11, reactive eosinophilia n = 3). Results Contrary to published literature, we found no difference in the levels of the lncRNA Morrbid and its target BIM. Yet, we identified a near complete loss of expression of pro-apoptotic PUMA as well as a reduction in anti-apoptotic BCL-2. Accordingly, BCL-2 inhibition using venetoclax failed to achieve cell death induction in eosinophil granulocytes and bone marrow mononuclear cells from patients with hypereosinophilia. In contrast, MCL1 inhibition using S63845 specifically decreased the viability of bone marrow progenitor cells in patients with hypereosinophilia. In patients diagnosed with Chronic Eosinophilic Leukemia (CEL-NOS) or Myeloid and Lymphatic Neoplasia with hypereosinophilia (MLN-Eo) repression of survival was specifically powerful. Conclusion Our study shows that MCL1 inhibition might be a promising therapeutic option for hypereosinophilia patients specifically for CEL-NOS and MLN-Eo.

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