Abstract 47: Age of Donor of Human Mesenchymal Stem Cells Drastically Affects Structural and Functional Recovery After Cell Therapy Following Ischemic Stroke

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Susumu Yamaguchi ◽  
Nobutaka Horie ◽  
Katsuya Satoh ◽  
Yoichi Morofuji ◽  
Tsuyoshi Izumo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cell Migration ◽  
Ischemic Stroke ◽  
Functional Recovery ◽  
Human Mesenchymal Stem Cells ◽  
Trophic Factor ◽  
Donor Age ◽  
Vessel Maturation ◽  
Factor Secretion

Background and purpose: Cell transplantation therapy holds great potential to improve impairments after stroke. However, the importance of donor age on therapeutic efficacy is uncertain. We investigate regenerative capacity of transplanted cells focusing on donor age (young vs. old) for ischemic stroke. Methods: The value of platelet-derived growth factor (PDGF)-BB secreted from human mesenchymal stem cells (hMSC) was analyzed regarding in two age groups; young (20-30 years) and old (57-65 years) in vitro. Male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion, and received young or old hMSC trans-arterially at 24 h after stroke. Functional recovery was assessed with modified neurological severity score (mNSS). Structural recovery was assessed on neovascularization and endogenous cell migration as well as trophic factor secretion. Results: The value of PDGF-BB was significantly higher in young hMSC (40.47±4.29 pg/ml/10 4 cells) than that in old hMSC (25.35±3.16 pg/ml/10 4 cells; P =0.02) and negatively correlated with age ( P =0.048, r=-0.79, Spearman). Rats treated with young hMSC (3.7±0.6) showed better behavior recovery in mNSS with prevention of brain atrophy than that with control (6.1±0.5) or old (5.2±0.7) at D21 ( P <0.01). The number of RECA-1 and PDGFR-β double positive vessels in rat with young hMSC (113±48.6/mm 2 ) was higher than that in control (61.5±35.9/mm 2 ) or old (76.9±36.9/mm 2 ) suggesting vessel maturation ( P <0.01). Interestingly, migration of neural stem/progenitor cells expressing Musashi-1 positively correlated with astrocyte process alignment ( P <0.01, r=0.27; Spearman), which was more pronounced in young hMSC ( P <0.05). Conclusions: Aging of hMSC may be the critical factor which affects outcome of cell therapy, and transplantation of young hMSC could provide better functional recovery by vessel maturation and endogenous cell migration potentially due to dominance of trophic factor secretion.

MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines

Blood ◽  
2007 ◽  
Vol 109 (9) ◽  
pp. 4055-4063 ◽  
Author(s):  
Christian Ries ◽  
Virginia Egea ◽  
Marisa Karow ◽  
Helmut Kolb ◽  
Marianne Jochum ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cell Migration ◽  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Human Mesenchymal Stem Cells ◽  
Basement Membranes ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Matrix Metalloproteinase 2

Abstract Human mesenchymal stem cells (hMSCs) represent promising tools in various clinical applications, including the regeneration of injured tissues by endogenous or transplanted hMSCs. The molecular mechanisms, however, that control hMSC mobilization and homing which require invasion through extracellular matrix (ECM) barriers are almost unknown. We have analyzed bone marrow–derivedhMSCs and detected strong expression and synthesis of matrix metalloproteinase 2 (MMP-2), membrane type 1 MMP (MT1-MMP), tissue inhibitor of metalloproteinase 1 (TIMP-1), and TIMP-2. The ability of hMSCs to traverse reconstituted human basement membranes was effectively blocked in the presence of synthetic MMP inhibitors. Detailed studies by RNA interference revealed that gene knock-down of MMP-2, MT1-MMP, or TIMP-2 substantially impaired hMSC invasion, whereas silencing of TIMP-1 enhanced cell migration, indicating opposing roles of both TIMPs in this process. Moreover, the inflammatory cytokines TGF-β1, IL-1β, and TNF-α up-regulated MMP-2, MT1-MMP, and/or MMP-9 production in these cells, resulting in a strong stimulation of chemotactic migration through ECM, whereas the chemokine SDF-1α exhibited minor effects on MMP/TIMP expression and cell invasion. Thus, induction of specific MMP activity in hMSCs by inflammatory cytokines promotes directed cell migration across reconstituted basement membranes in vitro providing a potential mechanism in hMSC recruitment and extravasation into injured tissues in vivo.

Abstract 3420: Potential of Human Mesenchymal Stem Cells to Differentiate into Cardiomyocytes Depends on Donor Age and Donor Tissue

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
John Van Tuyn ◽  
Daniel A Pijnappels ◽  
Marlieke L Haeck ◽  
Shoshan Knaän-Shanzer ◽  
Sicco Scherjon ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Cell Therapy ◽  
Cord Blood ◽  
Umbilical Cord Blood ◽  
Human Mesenchymal Stem Cells ◽  
Cardiac Cell ◽  
Donor Age ◽  
Cardiac Cell Therapy

Treatment of damaged myocardium using autologous adult stem cells is under intense investigation as this may regenerate lost myocardium, thereby improving cardiac function. Initial cardiac cell therapy trials using various adult stem cell types have shown beneficial effects. However in contrast to earlier animal studies no true, quantitative reconstitution of myocardium has been observed. We hypothesized that the cardiomyogenic potential of stem cells depends on donor age and cell source. We used an in vitro differentiation protocol that employs co-culture of enhanced green fluorescent protein-labeled human mesenchymal stem cells (hMSCs) with neonatal rat cardiomyocytes (nrCMCs) for 13 days, without additional chemical or mutagenic stimulation. hMSCs were either derived from adult patients, or from human fetal tissue (gestational age 18 –22 weeks) or post natally collected umbilical cord blood. Differentiation of hMSCs was assessed by the presence of a properly developed sarcomere using immunological labeling for cardiac troponin I, myosin heavy chain and actinin. Functionality of newly differentiated cardiomyocytes was assessed by the presence of a functional calcium transient in conjunction with myocyte contraction. Mesenchymal stem cells isolated from clinically relevant sources (bone marrow, fat, and synovium) of adult patients are unable to adopt a cardiomyocyte phenotype upon co-incubation with nrCMCs. In contrast, MSCs from fetal donor material all give rise to functional cardiomyocytes, although with varying efficiency (umbilical cord blood: 6.8%±3.0, bone marrow: 0.4%±1.4, liver: 1.8%±0.8, lung: 1.4%±1.3, amnion: 9.3%±5.0 [mean±SD, n=3]). Using short hairpin RNA-mediated knockdown of connexin 43 (Cx43) gene expression, we found that sarcomeric development (organization) depends on the presence of Cx43 in the differentiating stem cells. Both donor age and the tissue source of human MSCs critically influence their cardiomyogenic differentiation potential. These results suggest that these non-embryonic, fetal cells may potentially be clinically useful for cardiac cell therapy.

scholarly journals Mesenchymal Stem Cells Expressing Brain-Derived Neurotrophic Factor Enhance Endogenous Neurogenesis in an Ischemic Stroke Model

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Chang Hyun Jeong ◽  
Seong Muk Kim ◽  
Jung Yeon Lim ◽  
Chung Heon Ryu ◽  
Jin Ae Jun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Ischemic Stroke ◽  
Functional Recovery ◽  
Subventricular Zone ◽  
Neurotrophic Factor ◽  
Therapeutic Potential ◽  
Brain Derived Neurotrophic Factor ◽  
Neurological Deficits ◽  
Therapeutic Benefits

Numerous studies have reported that mesenchymal stem cells (MSCs) can ameliorate neurological deficits in ischemic stroke models. Among the various hypotheses that have been suggested to explain the therapeutic mechanism underlying these observations, neurogenesis is thought to be critical. To enhance the therapeutic benefits of human bone marrow-derived MSCs (hBM-MSCs), we efficiently modified hBM-MSCs by introduction of the brain-derived neurotrophic factor (BDNF) gene via adenoviral transduction mediated by cell-permeable peptides and investigated whetherBDNF-modified hBM-MSCs (MSCs-BDNF) contributed to functional recovery and endogenous neurogenesis in a rat model of middle cerebral artery occlusion (MCAO). Transplantation of MSCs induced the proliferation of 5-bromo-2′-deoxyuridine (BrdU-) positive cells in the subventricular zone. Transplantation of MSCs-BDNF enhanced the proliferation of endogenous neural stem cells more significantly, while suppressing cell death. Newborn cells differentiated into doublecortin (DCX-) positive neuroblasts and Neuronal Nuclei (NeuN-) positive mature neurons in the subventricular zone and ischemic boundary at higher rates in animals with MSCs-BDNF compared with treatment using solely phosphate buffered saline (PBS) or MSCs. Triphenyltetrazolium chloride staining and behavioral analysis revealed greater functional recovery in animals with MSCs-BDNF compared with the other groups. MSCs-BDNF exhibited effective therapeutic potential by protecting cell from apoptotic death and enhancing endogenous neurogenesis.

Transplants of Human Mesenchymal Stem Cells Improve Functional Recovery After Spinal Cord Injury in the Rat

2006 ◽  
Vol 26 (7-8) ◽  
pp. 1165-1178 ◽  
Author(s):  
Daša Čížková ◽  
Ján Rosocha ◽  
Ivo Vanický ◽  
Stanislava Jergová ◽  
Milan Čížek
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Spinal Cord Injury ◽  
Mesenchymal Stem Cells ◽  
Functional Recovery ◽  
Human Mesenchymal Stem Cells ◽  
Cord Injury

scholarly journals Basement membrane proteins modulate cell migration on bovine pericardium extracellular matrix scaffold

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Qi Xing ◽  
Mojtaba Parvizi ◽  
Manuela Lopera Higuita ◽  
Leigh G. Griffiths
Keyword(s):  
Stem Cells ◽  
Monoclonal Antibody ◽  
Extracellular Matrix ◽  
Mesenchymal Stem Cells ◽  
Cell Migration ◽  
Basement Membrane ◽  
Type I Collagen ◽  
Human Mesenchymal Stem Cells ◽  
Bovine Pericardium ◽  
Type I

AbstractNative bovine pericardium (BP) exhibits anisotropy of its surface ECM niches, with the serous surface (i.e., parietal pericardium) containing basement membrane components (e.g., Laminin, Col IV) and the fibrous surface (i.e., mediastinal side) being composed primarily of type I collagen (Col I). Native BP surface ECM niche anisotropy is preserved in antigen removed BP (AR-BP) extracellular matrix (ECM) scaffolds. By exploiting sideness (serous or fibrous surface) of AR-BP scaffolds, this study aims to determine the mechanism by which ECM niche influences human mesenchymal stem cells (hMSCs) migration. Human mesenchymal stem cells (hMSC) seeding on serous surface promoted more rapid cell migration than fibrous surface seeding. Gene analysis revealed that expression of integrin α3 and α11 were increased in cells cultured on serous surface compared to those on the fibrous side. Monoclonal antibody blockade of α3β1 (i.e., laminin binding) inhibited early (i.e. ≤ 6 h) hMSC migration following serous seeding, while having no effect on migration of cells on the fibrous side. Blockade of α3β1 resulted in decreased expression of integrin α3 by cells on serous surface. Monoclonal antibody blockade of α11β1 (i.e., Col IV binding) inhibited serous side migration at later time points (i.e., 6–24 h). These results confirmed the role of integrin α3β1 binding to laminin in mediating early rapid hMSCs migration and α11β1 binding to Col IV in mediating later hMSCs migration on the serous side of AR-BP, which has critical implications for rate of cellular monolayer formation and use of AR-BP as blood contacting material for clinical applications.

Preparation of inorganic-organic hybrid membrane for peripheral nerve reconstruction

2013 ◽  
Vol 2013 (CICMT) ◽  
pp. 000173-000176
Author(s):  
Yuki Shirosaki ◽  
Satoshi Hayakawa ◽  
Akiyoshi Osaka ◽  
Maria A. Lopes ◽  
José D. Santos ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Peripheral Nerve ◽  
Functional Recovery ◽  
Human Mesenchymal Stem Cells ◽  
Hybrid Membrane ◽  
Human Mscs ◽  
Hybrid Membranes ◽  
Nerve Reconstruction ◽  
Porous Chitosan

The treatment of peripheral nerve injuries is still one of the most challenging tasks in neurosurgery, as functional recovery is rarely satisfactory in these patients. The concept behind the use of biodegradable nerve guides is that no foreign material should be left in place after the device has fulfilled its task, so as to spare a second surgical intervention. In a previous study, flexible and biodegradable chitosan-3-glycidoxypropyltrimethoxysilane (GPTMS) hybrid membranes exhibited better cytocompatibility in terms of osteoblastic cells than chitosan membrane. Porous chitosan hybrid membranes, derived by freeze-drying the hybrid gels, showed that the cells were attached and proliferated both on the surface and into pores. In this study, the porous chitosan-silicate hybrid membranes with non-differentiated human mesenchymal stem cells isolated from Wharton's jelly of umbilical cord were used to reconstruct the crushed peripheral nerve. Axonotmesis lesion of 3 mm was enwrapped with the hybrid membranes with or without a monolayer of non-differentiated human mesenchymal stem cells. Motor and sensory functional recovery was evaluated throughout a healing period of 12 weeks. The combination of hybrid membranes and human MSCs infiltration showed a slightly better recovery than the untreated control (the just crushed nerve). On the other hand, the hybrid membrane alone promoted the crushed peripheral nerve reconstruction. It is expected that the porous chitosan hybrid membranes is candidate for the clinical tool in peripheral nerve reconstructive surgery.

Sign in / Sign up

Export Citation Format

Share Document