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Cybermedlife - Therapeutic Actions Stem Cell Related Therapy

Stem cell factor-activated bone marrow ameliorates amyotrophic lateral sclerosis by promoting protective microglial migration. 📎

Abstract Title: Stem cell factor-activated bone marrow ameliorates amyotrophic lateral sclerosis by promoting protective microglial migration. Abstract Source: J Neurosci Res. 2014 Jul ;92(7):856-69. PMID: 24936617 Abstract Author(s): Tomoya Terashima, Hideto Kojima, Hiroshi Urabe, Isamu Yamakawa, Nobuhiro Ogawa, Hiromichi Kawai, Lawrence Chan, Hiroshi Maegawa Article Affiliation: Tomoya Terashima Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive disease associated with motor neuron death. Several experimental treatments, including cell therapy using hematopoietic or neuronal stem cells, have been tested in ALS animal models, but therapeutic benefits have been modest. Here we used a new therapeutic strategy, bone marrow transplantation (BMT) with stem cell factor (SCF)- or FMS-like tyrosine kinase 3 (flt3)-activated bone marrow (BM) cells for the treatment of hSOD1(G93A) transgenic mice. Motor function and survival showed greater improvement in the SCF group than in the group receiving BM cells that had not been activated (BMT alone group), although no improvement was shown in the flt3 group. In addition, larger numbers of BM-derived cells that expressed the microglia marker Iba1 migrated to the spinal cords of recipient mice compared with the BMT alone group. Moreover, after SCF activation, but not flt3 activation or no activation, the migrating microglia expressed glutamate transporter-1 (GLT-1). In spinal cords in the SCF group, inflammatory cytokines tumor necrosis factor-α and interleukin-1β were suppressed and the neuroprotective molecule insulin-like growth factor-1 increased relative to nontreatment hSOD1(G93A) transgenic mice. Therefore, SCF activation changed the character of the migrating donor BM cells, which resulted in neuroprotective effects. These studies have identified SCF-activated BM cells as a potential new therapeutic agent for the treatment of ALS. Article Published Date : Jun 30, 2014

Systemic treatment with adipose-derived mesenchymal stem cells ameliorates clinical and pathological features in the amyotrophic lateral sclerosis murine model.

Abstract Title: Systemic treatment with adipose-derived mesenchymal stem cells ameliorates clinical and pathological features in the amyotrophic lateral sclerosis murine model. Abstract Source: Neuroscience. 2013 May 28 ;248C:333-343. Epub 2013 May 28. PMID: 23727509 Abstract Author(s): S Marconi, M Bonaconsa, I Scambi, G M Squintani, W Rui, E Turano, D Ungaro, S D'Agostino, F Barbieri, S Angiari, A Farinazzo, G Constantin, U Del Carro, B Bonetti, R Mariotti Article Affiliation: S Marconi Abstract: Therapeutic strategies for the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) are actually minimally effective on patients' survival and quality of life. Although stem cell therapy has raised great expectations, information on the involved molecular mechanisms is still limited. Here we assessed the efficacy of the systemic administration of adipose-derived mesenchymal stem cells (ASC), a previously untested stem cell population, in superoxide-dismutase 1 (SOD1)-mutant transgenic mice, the animal model of familial ALS. The administration of ASC to SOD1-mutant mice at the clinical onset significantly delayed motor deterioration for 4-6weeks, as shown by clinical and neurophysiological tests. Neuropathological examination of ASC-treated SOD1-mutant mice at day 100 (i.e. the time of their best motor performance) revealed a higher number of lumbar motorneurons than in phosphate-buffered saline-treated SOD1-mutant mice and a restricted number of undifferentiated green fluorescent protein-labeled ASC in the spinal cord. By examining the spinal cord tissue factors that may prolong neuronal survival, we found a significant up-regulation in levels of glial-derived neurotrophic factor (GDNF) and basic fibroblast growth factor (bFGF) after ASC treatment. Considering that ASC produce bFGF but not GDNF, these findings indicate that ASC may promote neuroprotection either directly and/or by modulating the secretome of local glial cells toward a neuroprotective phenotype. Such neuroprotection resulted in a strong and long-lasting effect on motor performance and encourages the use of ASC in human pathologies, in which current therapies are not able to maintain a satisfying neurological functional status. Article Published Date : May 27, 2013

Linking respiratory chain uncoupling to amyotrophic lateral sclerosis implies potential treatment with herbal extracts containing genipin.

Abstract Title: Linking respiratory chain uncoupling to amyotrophic lateral sclerosis implies potential treatment with herbal extracts containing genipin. Abstract Source: Med Hypotheses. 2013 Mar ;80(3):327. Epub 2012 Dec 21. PMID: 23265356 Abstract Author(s): M Hoffmann Article Affiliation: M Hoffmann Abstract: No abstract. Article Published Date : Feb 28, 2013

Neural progenitors derived from human induced pluripotent stem cells survive and differentiate upon transplantation into a rat model of amyotrophic lateral sclerosis. 📎

Abstract Title: Neural progenitors derived from human induced pluripotent stem cells survive and differentiate upon transplantation into a rat model of amyotrophic lateral sclerosis. Abstract Source: Stem Cells Transl Med. 2013 Mar ;2(3):167-74. Epub 2013 Feb 14. PMID: 23413376 Abstract Author(s): Iuliana Ristea Popescu, Charles Nicaise, Song Liu, Grégoire Bisch, Sarah Knippenberg, Valery Daubie, Delphine Bohl, Roland Pochet Article Affiliation: Iuliana Ristea Popescu Abstract: Human induced pluripotent stem cells (iPSCs) offer hope for personalized regenerative cell therapy in amyotrophic lateral sclerosis (ALS). We analyzed the fate of human iPSC-derived neural progenitors transplanted into the spinal cord of wild-type and transgenic rats carrying a human mutated SOD1(G93A) gene. The aim was to follow survival and differentiation of human neural progenitors until day 60 post-transplantation in two different in vivo environments, one being ALS-like. iPSC-derived neural progenitors efficiently engrafted in the adult spinal cord and survived at high numbers. Different neural progenitor, astroglial, and neuronal markers indicated that, over time, the transplanted nestin-positive cells differentiated into cells displaying a neuronal phenotype in both wild-type and transgenic SOD1 rats. Although a transient microglial phenotype was detected at day 15, astroglial staining was negative in engrafted cells from day 1 to day 60. At day 30, differentiation toward a neuronal phenotype was identified, which was further established at day 60 by the expression of the neuronal marker MAP2. A specification process into motoneuron-like structures was evidenced in the ventral horns in both wild-type and SOD1 rats. Our results demonstrate proof-of-principle of survival and differentiation of human iPSC-derived neural progenitors in in vivo ALS environment, offering perspectives for the use of iPSC-based therapy in ALS. Article Published Date : Feb 28, 2013

Intermittent hypoxia and stem cell implants preserve breathing capacity in a rodent model of amyotrophic lateral sclerosis. 📎

Abstract Title: Intermittent hypoxia and stem cell implants preserve breathing capacity in a rodent model of amyotrophic lateral sclerosis. Abstract Source: Am J Respir Crit Care Med. 2013 Mar 1 ;187(5):535-42. Epub 2012 Dec 6. PMID: 23220913 Abstract Author(s): Nicole L Nichols, Genevieve Gowing, Irawan Satriotomo, Lisa J Nashold, Erica A Dale, Masatoshi Suzuki, Pablo Avalos, Patrick L Mulcrone, Jacalyn McHugh, Clive N Svendsen, Gordon S Mitchell Article Affiliation: Nicole L Nichols Abstract: RATIONALE: Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease causing paralysis and death from respiratory failure. Strategies to preserve and/or restore respiratory function are critical for successful treatment. Although breathing capacity is maintained until late in disease progression in rodent models of familial ALS (SOD1(G93A) rats and mice), reduced numbers of phrenic motor neurons and decreased phrenic nerve activity are observed. Decreased phrenic motor output suggests imminent respiratory failure. OBJECTIVES: To preserve or restore phrenic nerve activity in SOD1(G93A) rats at disease end stage. METHODS: SOD1(G93A) rats were injected with human neural progenitor cells (hNPCs) bracketing the phrenic motor nucleus before disease onset, or exposed to acute intermittent hypoxia (AIH) at disease end stage. MEASUREMENTS AND MAIN RESULTS: The capacity to generate phrenic motor output in anesthetized rats at disease end stage was: (1) transiently restored by a single presentation of AIH; and (2) preserved ipsilateral to hNPC transplants made before disease onset. hNPC transplants improved ipsilateral phrenic motor neuron survival. CONCLUSIONS: AIH-induced respiratory plasticity and stem cell therapy have complementary translational potential to treat breathing deficits in patients with ALS. Article Published Date : Feb 28, 2013

Cultivating stem cells for treating amyotrophic lateral sclerosis. 📎

Abstract Title: Cultivating stem cells for treating amyotrophic lateral sclerosis. Abstract Source: World J Stem Cells. 2012 Dec 26 ;4(12):117-9. PMID: 23516096 Abstract Author(s): Shengwen Calvin Li, Hong Zhen Yin, William G Loudon, John H Weiss Article Affiliation: Shengwen Calvin Li Abstract: This editorial addresses the current challenges and future directions in the use of stem cells as an approach for treating amyotrophic lateral sclerosis. A wide variety of literature has been reviewed to enlighten the reader on the many facets of stem cell research that are important to consider before using them for a cell based therapy. Article Published Date : Dec 25, 2012

Autologous bone marrow-derived stem cells in amyotrophic lateral sclerosis: a pilot study. 📎

Abstract Title: Autologous bone marrow-derived stem cells in amyotrophic lateral sclerosis: a pilot study. Abstract Source: Neurol India. 2012 Sep-Oct;60(5):465-9. PMID: 23135021 Abstract Author(s): Sudesh Prabhakar, Neelam Marwaha, Vivek Lal, Ratti R Sharma, Roopa Rajan, Niranjan Khandelwal Article Affiliation: Sudesh Prabhakar Abstract: BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no effective treatment. Stem cell therapy may be one of the promising treatment options for such patients. AIM: To assess the feasibility, efficacy and safety of autologous bone marrow-derived stem cells in patients of ALS. SETTINGS AND DESIGN: We conducted an open-label pilot study of autologous bone marrow-derived stem cells in patients with ALS attending the Neurology Clinic of a tertiary care referral centre. MATERIALS AND METHODS: Ten patients with ALS with mean revised ALS Functional Rating Scale (ALSFRS-R) score of 30.2 (± 10.58) at baseline received intrathecal autologous bone marrow-derived stem cells. Primary end point was improvement in the ALSFRS-R score at 90, 180, 270 and 365 days post therapy. Secondary endpoints included ALSFRS-R subscores, time to 4-point deterioration, median survival and reported adverse events. Paired t-test was used to compare changes in ALSFRS-R from baseline and Kaplan-Meier analysis was used for survival calculations. RESULTS: There was no significant deterioration in ALSFRS-R composite score from baseline at one-year follow-up (P=0.090). The median survival post procedure was 18.0 months and median time to 4-point deterioration was 16.7 months. No significant adverse events were reported. CONCLUSION: Autologous bone marrow-derived stem cell therapy is safe and feasible in patients of ALS. Short-term follow-up of ALSFRS-R scores suggests a trend towards stabilization of disease. However, the benefit needs to be confirmed in the long-term follow-up period. Article Published Date : Aug 31, 2012
Therapeutic Actions Stem Cell Related Therapy

NCBI pubmed

High-dose melphalan and autologous peripheral blood stem cell transplantation in patients with AL amyloidosis and cardiac defibrillators.

Related Articles High-dose melphalan and autologous peripheral blood stem cell transplantation in patients with AL amyloidosis and cardiac defibrillators. Bone Marrow Transplant. 2019 Jan 21;: Authors: Phull P, Sanchorawala V, Brauneis D, Sloan JM, Siddiqi OK, Quillen K, Sarosiek S Abstract Cardiac deposition of misfolded light chains is the leading cause of morbidity and mortality in patients with immunoglobulin (AL) amyloidosis. Cardiac defibrillators can be used in the management of patients with advanced cardiac amyloidosis, but data concerning the use of these devices in patients undergoing treatment with high-dose melphalan followed by autologous peripheral blood stem cell transplantation (HDM/SCT) is limited. Herein we describe a single-institution experience of HDM/SCT in 15 patients with cardiac defibrillators. During the peri-transplant period, five of these patients (33%) had detectable cardiac arrhythmias and two patients (13%) had implantable cardiac defibrillator (ICD) discharges. Thirteen of the 14 evaluable patients (93%) achieved at least a partial hematologic response. Transplant-related mortality was 6.7% and median overall survival was 40.8 months, with multiple patients achieving an overall survival of >10 years. These data highlight the feasibility of HDM/SCT in patients with an ICD due to advanced cardiac AL amyloidosis, but highlight the need for additional research to appropriately determine which patients will benefit from this aggressive therapy. PMID: 30664726 [PubMed - as supplied by publisher]

Circular RNA circ_0001946 acts as a competing endogenous RNA to inhibit glioblastoma progression by modulating miR-671-5p and CDR1.

Related Articles Circular RNA circ_0001946 acts as a competing endogenous RNA to inhibit glioblastoma progression by modulating miR-671-5p and CDR1. J Cell Physiol. 2019 Jan 21;: Authors: Li X, Diao H Abstract OBJECTIVES: In many malignant tumors, circRNAs play an important role. However, the biological role and clinical significance of circRNAs remain unclear. In this study, we investigated the effects of circ_0001946 on the progression of glioblastoma (GBM) and the molecular mechanism of circ_0001946. METHODS: Microarrays were applied to test the expression profiles of circRNAs and messenger RNAs (mRNAs). Coexpressed genes were identified by constructing differentially expressed circRNA-mRNA networks. The expression of circ_0001946, miR-671-5p, and cerebellar degeneration-related autoantigen 1 (CDR1) was detected by real-time quantitative PCR, and the protein expression of CDR1 was determined by western blotting. A dual-luciferase reporter assay was used to evaluate potential miR-671-5p target sites on circ_0001946 and CDR1. The proliferation, apoptosis, migration, and invasion of GBM cells were assessed by a colony formation assay, flow cytometry assay, transwell migration assay, and transwell invasion assay. Xenograft mouse models were used to determine the role of circ_0001946 in vivo. RESULTS: The expression of circ_0001946 and CDR1 was low and that of miR-671-5p was high in GBM cells. Circ_0001946 suppressed the expression of miR-671-5p, thus upregulating the expression of CDR1, the gene downstream of miR-671-5p. Circ_0001946 and CDR1 reduced proliferation, migration, and invasion and increased apoptosis in GBM cells, whereas miR-671-5p had an opposite effect. The xenograft mouse model and immunohistochemistry results indicated that circ_0001946 inhibited GBM growth as well as the expression of Ki67 in GBM cells. CONCLUSION: Our study confirmed that the circ_0001946/miR-671-5p/ CDR1 pathway modulates the development of GBM, and this pathway might be a promising target for the development of therapeutics for GBM. PMID: 30663767 [PubMed - as supplied by publisher]

Exosomes from human umbilical cord mesenchymal stem cells enhance fracture healing through HIF-1α-mediated promotion of angiogenesis in a rat model of stabilized fracture.

Related Articles Exosomes from human umbilical cord mesenchymal stem cells enhance fracture healing through HIF-1α-mediated promotion of angiogenesis in a rat model of stabilized fracture. Cell Prolif. 2019 Jan 20;:e12570 Authors: Zhang Y, Hao Z, Wang P, Xia Y, Wu J, Xia D, Fang S, Xu S Abstract OBJECTIVES: Exosomes, as important players in intercellular communication due to their ability to transfer certain molecules to target cells, are believed to take similar effects in promoting bone regeneration with their derived stem cells. Studies have suggested that umbilical cord mesenchymal stem cells (uMSCs) could promote angiogenesis. This study investigated whether exosomes derived from uMSCs (uMSC-Exos) could enhance fracture healing as primary factors by promoting angiogenesis. MATERIALS AND METHODS: uMSCs were obtained to isolate uMSC-Exos by ultrafiltration, with exosomes from human embryonic kidney 293 cells (HEK293) and phosphate-buffered saline (PBS) being used as control groups. NanoSight, laser light scattering spectrometer, transmission electron microscopy and Western blotting were used to identify exosomes. Next, uMSC-Exos combined with hydrogel were transplanted into the fracture site in a rat model of femoral fracture. Bone healing processes were monitored and evaluated by radiographic methods on days 7, 14, 21 and 31 after surgery; angiogenesis of the fracture sites was assessed by radiographic and histological strategies on post-operative day 14. In vitro, the expression levels of osteogenesis- or angiogenesis-related genes after being cultured with uMSC-Exos were identified by qRT-PCR. The internalization ability of exosomes was determined using the PKH67 assay. Cell cycle analysis, EdU incorporation and immunofluorescence staining, scratch wound assay and tube formation analysis were also used to determine the altered abilities of human umbilical vein endothelial cells (HUVECs) administered with uMSC-Exos in proliferation, migration and angiogenesis. Finally, to further explore the underlying molecular mechanisms, specific RNA inhibitors or siRNAs were used, and the subsequent effects were observed. RESULTS: uMSC-Exos had a diameter of approximately 100 nm, were spherical, meanwhile expressing CD9, CD63 and CD81. Transplantation of uMSC-Exos markedly enhanced angiogenesis and bone healing processes in a rat model of femoral fracture. In vitro, other than enhancing osteogenic differentiation, uMSC-Exos increased the expression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1α (HIF-1α). uMSC-Exos were taken up by HUVECs and enhanced their proliferation, migration and tube formation. Finally, by using specific RNA inhibitors or siRNAs, it has been confirmed that HIF-1α played an important role in the uMSC-Exos-induced VEGF expression, pro-angiogenesis and enhanced fracture repair, which may be one of the underlying mechanisms. CONCLUSIONS: These results revealed a novel role of exosomes in uMSC-mediated therapy and suggested that implanted uMSC-Exos may represent a crucial clinical strategy to accelerate fracture healing via the promotion of angiogenesis. HIF-1α played an important role in this process. PMID: 30663158 [PubMed - as supplied by publisher]

The Potential of Isoprenoids in Adjuvant Cancer Therapy to Reduce Adverse Effects of Statins.

Related Articles The Potential of Isoprenoids in Adjuvant Cancer Therapy to Reduce Adverse Effects of Statins. Front Pharmacol. 2018;9:1515 Authors: Mo H, Jeter R, Bachmann A, Yount ST, Shen CL, Yeganehjoo H Abstract The mevalonate pathway provides sterols for membrane structure and nonsterol intermediates for the post-translational modification and membrane anchorage of growth-related proteins, including the Ras, Rac, and Rho GTPase family. Mevalonate-derived products are also essential for the Hedgehog pathway, steroid hormone signaling, and the nuclear localization of Yes-associated protein and transcriptional co-activator with PDZ-binding motif, all of which playing roles in tumorigenesis and cancer stem cell function. The phosphatidylinositol-4,5-bisphosphate 3-kinase-AKT-mammalian target of rapamycin complex 1 pathway, p53 with gain-of-function mutation, and oncoprotein MYC upregulate the mevalonate pathway, whereas adenosine monophosphate-activated protein kinase and tumor suppressor protein RB are the downregulators. The rate-limiting enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), is under a multivalent regulation. Sterol regulatory element binding protein 2 mediates the sterol-controlled transcriptional downregulation of HMGCR. UbiA prenyltransferase domain-containing protein-1 regulates the ubiquitination and proteasome-mediated degradation of HMGCR, which is accelerated by 24, 25-dihydrolanosterol and the diterpene geranylgeraniol. Statins, competitive inhibitors of HMGCR, deplete cells of mevalonate-derived intermediates and consequently inhibit cell proliferation and induce apoptosis. Clinical application of statins is marred by dose-limiting toxicities and mixed outcomes on cancer risk, survival and mortality, partially resulting from the statin-mediated compensatory upregulation of HMGCR and indiscriminate inhibition of HMGCR in normal and tumor cells. Tumor HMGCR is resistant to the sterol-mediated transcriptional control; consequently, HMGCR is upregulated in cancers derived from adrenal gland, blood and lymph, brain, breast, colon, connective tissue, embryo, esophagus, liver, lung, ovary, pancreas, prostate, skin, and stomach. Nevertheless, tumor HMGCR remains sensitive to isoprenoid-mediated degradation. Isoprenoids including monoterpenes (carvacrol, L-carvone, geraniol, perillyl alcohol), sesquiterpenes (cacalol, farnesol, β-ionone), diterpene (geranylgeranyl acetone), "mixed" isoprenoids (tocotrienols), and their derivatives suppress the growth of tumor cells with little impact on non-malignant cells. In cancer cells derived from breast, colon, liver, mesothelium, prostate, pancreas, and skin, statins and isoprenoids, including tocotrienols, geraniol, limonene, β-ionone and perillyl alcohol, synergistically suppress cell proliferation and associated signaling pathways. A blend of dietary lovastatin and δ-tocotrienol, each at no-effect doses, suppress the growth of implanted murine B16 melanomas in C57BL6 mice. Isoprenoids have potential as adjuvant agents to reduce the toxicities of statins in cancer prevention or therapy. PMID: 30662405 [PubMed]

[Advances in the research of influence of diabetes in biological function of adipose-derived stem cells].

Related Articles [Advances in the research of influence of diabetes in biological function of adipose-derived stem cells]. Zhonghua Shao Shang Za Zhi. 2018 Sep 20;34(9):653-656 Authors: Yao YZ, Deng CL, Wang B Abstract Adipose-derived stem cells (ADSCs) are adult mesenchymal stem cells in adipose tissue with self-renewal and multi-directional differentiation potential. The application of ADSCs in the treatment of wounds has achieved good results. Because of its extensive sources, high content in vivo, low immunogenicity, slight injury to body when obtained, the clinical application prospect of ADSCs is promising. The reasons why diabetic wound is difficult to heal may be closely related to the increase of advanced glycation end products, long-term chronic inflammatory response, and peripheral neurologic dysfunction. The abnormal internal environment of diabetic patients can affect the biological function of ADSCs, which further affects wound healing. This article reviews the general feature, differentiation, proliferation, migration, secretion, and pro-angiogenic function of diabetic ADSCs. PMID: 30293371 [PubMed - indexed for MEDLINE]
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