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Mesenchymal Stem Cells

Stem Cell Prevention but Not Stem Cell Repair?

"Injection of Vessel-Derived Stem Cells Prevents Dilated Cardiomyopathy and Promotes Angiogenesis and Endogenous Cardiac Stem Cell Proliferation in mdx/utrn−/− but Not Aged mdx Mouse Models for Duchenne Muscular Dystrophy"

Duchenne muscular dystrophy (DMD) is an X-linked muscle wasting disease affecting approximately 1/3,500 male live births (Emery) and results from mutations in the dystrophin gene. While advances in care have alleviated some aspects of the disease, dilated cardiomyopathy (DCM) incidence has increased. Several pharmacological agents are used to target the symptoms but they do not address the underlying absence of dystrophin or the loss of cardiomyocytes. One potentially exciting avenue of exploration is the transplantation of exogenous stem cells, which can restore dystrophin expression (Berry et al and Sampaolesi et al). Fetal cardiomyocytes (Koh et al) and skeletal muscle-derived stem cells (MDSCs) (Payne et al) have both been investigated after injection directly into the heart. Now, in a study in Stem Cells Translational Medicine, researchers from the group of Suzanne E. Berry at the University of Illinois, USA have studied a role for adult-derived aorta-derived mesoangioblasts (ADMs) in the restoration of dystrophin expression and prevention/alleviation of cardiomyopathy in dystrophin-deficient mdx mice. In this study they show that ADMs induce cardiac marker expression and delayed the onset of DCM in young mice, but could not reverse symptoms in older mice (Chun et al).

Co-culture Aids Robust Cartilage Differentiation

"Coculture-Driven Mesenchymal Stem Cell-Differentiated Articular Chondrocyte-Like Cells Support Neocartilage Development"

Mesenchymal stem cells (MSCs) are an attractive source for repair and regeneration of tissue or organ defects. Transplantation of MSCs into defective knee joints to restore cartilage function has yielded some success, although they have yet to pass the pre-clinical and phase I stages towards proper therapeutic use (Koga et al.). A greater understanding of in vivo MSC differentiation mechanisms could aid the widespread use of MSCs through the precise control of cell lineage during in vitro differentiation. Several bioactive agents, such as transforming growth factor-b (TGF-b), insulin-like growth factor-1 (IGF-1), bone morphogenetic protein-2 (BMP-2), and basic fibroblast growth factor (FGF-2), are essential for the chondrogenic differentiation of MSCs (Heng et al.). The mode of delivery of these factors to MSCs has been scrutinised using gradual delivery through means such as gene therapy (Pagnotto et al.) and polymeric vehicles for molecule release (Macdonald et al. and Shah et al.) which have been posited to more closely replicate in vivo conditions (Macdonald et al.). However, an easier method may be the co-culture of MSCs with primary chondrocytes which would secrete proteins such as TGF-b, IGF-1, BMP-2 and FGF-2 slowly over time at physiological concentrations. This has now been studied in detail by researchers from the laboratory of Gilda A. Barabino at the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA and published in Stem Cells Translational Medicine. The researchers found that co-culture mediated differentiation of MSCs with chondrocytes led to the development of robust neocartilage in a three-dimensional agarose system that resisted hypertrophic maturation and calcification (Yang, Lee and Barabino).

Towards Optimal Growth Conditions for MSCs

"Effects of Medium Supplements on Proliferation, Differentiation Potential, and In Vitro Expansion of Mesenchymal Stem Cells"

Mesenchymal stem cells (MSCs) are multipotent, self-renewing cells with the capacity to differentiate into cells of great therapeutic value (Pitteneger et al.) and are also relatively easy to isolate and cultivate in vitro. However, this long term growth may be detrimental to their overall therapeutic value and therefore optimal growth conditions are being sought. Towards this goal Gharibi and Hughes from King's College London, United Kingdom, in a study published in Stem Cells Translational Medicine, have carried out a comprehensive investigation into the effects of cytokines on the cultivation of MSCs in vitro and demonstrate that medium supplemented with fibroblast growth factor (FGF)-2, platelet-derived growth factor (PDGF)- BB, ascorbic acid (AA), and epidermal growth factor (EGF) leads to the enhancement of the in vitro expansion capacity of MSC cultures.

MSCs Sniff Out a Way to the Brain

"Intranasal Delivery of Neural Stem/Progenitor Cells: A Non-invasive Passage to Target Intracerebral Glioma"

The use of neural stem cells and neural progenitor cells (NSPCs) for various central nervous system (CNS) diseases is an emerging therapy which benefits from these cells restorative potential and their ability to preferentially migrate to sites of disease and injury (Muller et al.). However, cellular integration after surgical implantation of allogenic cells derived from embryonic, fetal, or adult tissue is low, while intravascular administration risks intracerebral tumours and increases the risk of accumulation in peripheral organs. This has led researchers from the laboratory of Nils Ole Schmidt at the University Medical Center Hamburg-Eppendorf, Germany to investigate another method of delivery of NSPCs; intranasal administration. The intranasal cavity provides a direct passage to the intracerebral compartment along olfactory pathways and has been used for the administration of drugs and cells previously (Dhuria et al. and Danielyan et al.). In this study, Reitza et al. show the rapid and targeted migration of NSPCs via intranasally accessible pathways toward the intracerebral compartment in a mouse model of intracerebral glioma.

Nanog Breathes New Life into Old Cells

Original article from STEM CELLS

"Nanog Reverses the Effects of Organismal Aging on Mesenchymal Stem Cell Proliferation and Myogenic Differentiation Potential"

Autologous mesenchymal stem cells (MSCs) are an attractive source of cells for use in a regenerative capacity, however several problems have arisen which may limit their extensive clinical use. These problems include the decrease number and quality of cells with increasing donor age (Caplan 2007, Han et al 2010 and Sethe et al) and the loss of proliferation and differentiation potential upon expansion in vitro (Banfi et al, Baxter et al and Bonab et al). Previous studies have found that expression of the pluripotency-associated gene Nanog in bone marrow derived MSCs (BM-MSCs) leads to accelerated growth and the enhancement of chondrogenic and osteogenic differentiation (Go et al and Liu et al). Now in a study published in Stem Cells, researchers from the laboratory of Stelios T. Andreadis from the University at Buffalo, State University of New York, USA have analysed the effects of ectopic expression of Nanog on BM-MSCs from older donors, and their results show that this can reverse the aging-mediated loss of proliferation and myogenic differentiation potential, partly mediated through activation of the TGF-β pathway (Han et al).

Signalling behind MSC Mobilisation Uncovered

Original article from STEM CELLS

“Injury-Activated Transforming Growth Factor β Controls Mobilization of Mesenchymal Stem Cells for Tissue Remodeling”

Adult stem/progenitor cells are able to differentiate into many cell types and can also be recruited to a site of injury where they either repair the injured tissue or contribute to tissue remodeling (Ferrari et al, Takahashi et al,Lagasse et al, Orlic et al and Kale et al). Mesenchymal stem cells (MSCs) in peripheral blood are one such stem cell known to act in this way, and it is believed that promigratory factors released from injured tissue or surrounding inflammatory cells create a signal for their recruitment (Caplan and Correa, Krankel et al and Wojakowski et al). However the primary endogenous factors activated or released in response to injury to stimulate the mobilization of MSCs are largely unknown. Transforming growth factor beta proteins (TGFβs) are synthesized in a latent form sequestered in extracellular matrix (ECM) (Kanzaki et al and Munger et al) and perturbations in the ECM associated with phenomena such as angiogenesis, wound repair, inflammation, and cell growth (Annes et al) release active TGFβs. TGFβ1 can be released from the bone matrix to induce MSCs migration for bone remodeling (Tang et al), but less is understood about a potential role in the vasculature where shear stress and arterial injury can induce activation of TGFβ1 (Ahamed et al and Qi et al). Now, in a study in Stem Cells, researchers from the group of Xu Cao at the Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, using two separate models of arterial damage, have found that MSCs become mobilized into peripheral blood and migrate to injured sites to participate in vascular repair and remodeling by a mechanism controlled by active TGFβ1 (Wan et al).

Stem Cell Transplant Down to a T - Mesenchymal stem cell–based tissue regeneration is governed by recipient T lymphocytes via IFNγ and TNFα

From Nature Medicine
By Stuart P. Atkinson

Bone marrow mesenchymal stem cells (BMMSCs) are multipotent adult stem cells which are capable of differentiating into various cell types (osteoblasts, adipocytes and chondrocytes (Friedenstein et al, Pittinger et al and Prockop)) and their regenerative capabilities shown to be of clinical importance in the treatment of bone and bone-associated tissue disease (Caplan, García-Gómez et al, Tasso et al and Bueno and Glowacki). Further, BMMSCs have been shown to interact with immune cells to aid bone regeneration but the specific function of recipient immune cells has not been assessed. Now, researchers from the laboratory of Songtao Shi at the University of Southern California, USA, have found that recipient immune cells, specifically T cells, govern BMMSC-based tissue regeneration using an established in vivo BMMSC implantation system (Liu et al).

Dedifferentiation-Reprogrammed Mesenchymal Stem Cells with Improved therapeutic Potential

Original article from STEM CELLS

Recent studies have demonstrated that mesenchymal stem cells (MSCs) have the ability to differentiate into various kinds of cell types, including neuron-like cells in culture (Woodbury et al, Qian and Saltzman, Levy et al and Rismanchi et al) which has been further verified by transplantation experiments in various animal models of human disease. However, these studies have been hampered by reported low levels of cell persistence, neuronal differentiation in vivo and massive death of transplanted cells limiting their overall effectiveness and clinical use. Dedifferentiation is a process by which differentiated cells are reverted to an earlier, more primitive phenotype which confers an extended differentiation potential (Odelberg, Kollhoff and Keating) and previous studies by the authors of the study discussed herein demonstrated that by withdrawal of extrinsic stimulation, MSC-derived neurons are able to revert back to MSC morphologically (Woodbury, Reynold and Black and Li et al), but whether these dedifferentiated MSCs (DeMSCs) were similar to MSCs was unknown. This point is now addressed in the December issue of Stem Cells in a study (Liu et al) from the laboratories of Hsiao Chang Chan (Chinese University of Hong Kong, Shatin, Hong Kong) and Tingyu Li (Chongqing Medical University, Chongqing, China).

Debrided Skin as a Source of Autologous Stem Cells for Wound Repair

From the August Edition of Stem Cells
Paper commentary by Stuart P. Atkinson

Tissue resident adult stem cells, such as mesenchymal stem cells (MSCs) or adipose-derived stem cells (ASCs), have previously demonstrated a capacity to repair extensively injured tissues (Picinich et al, Horwitz and Dominici). However, major traumatic injuries such as large surface area burns, which constitute 5%–10% of military casualties, limit the availability of autologous stem cell populations for wound repair and such injuries also require extensive reconstruction. The process of wound debridement; the medical removal of a patient's dead, damaged, or infected tissue to improve the healing potential of the remaining healthy tissue, typically involves the removal of subcutaneous layers and associated tissue structures, including portions of intact hypodermal adipose tissue. This led the group of Robert J. Christy at the United States Army Institute of Surgical Research, Fort Sam Houston, Texas, USA to investigate the potential of debrided skin to be a source of viable autologous stem cells for use in wound treatments. Their report (Natesan et al) is published in the August Edition of Stem Cells.


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