Mesenchymal Stem Cells

"Comparison of Drug and Cell-Based Delivery: Engineered Adult Mesenchymal Stem Cells Expressing Soluble Tumor Necrosis Factor Receptor II Prevent Arthritis in Mouse and Rat Animal Models"

Tumor necrosis factor-α (TNFα) is a cytokine that mediates normal homeostatic mammalian processes (Schaible et al and Wajant et al) but has been linked to the systemic autoimmune disease Rheumatoid Arthritis (RA), where a TNFα induced cytokine cascade causes inflammation and joint destruction. Blocking TNFα function would therefore seem a viable means to treat RA. Etanercept, a TNF receptor (TNFR) linked to the immunoglobin Fc fragment and two monoclonal antibodies, infliximab and adalimumab are three TNFα inhibitors approved in the United States (Mazza et al), while TNFα blockers certolizumab pegol and golimumab are also utilised (Wallis and Scallon et al). However, the necessity for systemic delivery leads to certain unwanted side-effects, and so site-specific drug action is being sought after. To this end, in a report in Stem Cells Translational Medicine, researchers led by Joseph D. Mosca at Osiris Therapeutics, Inc., Baltimore, Maryland, USA have published the results of their studies on the potential use of mesenchymal stem cell (MSC)-based TNFR delivery and the efficacy of this treatment compared to the use of etanercept (Liu et al).

 “Autologous Bone Marrow-Derived Mesenchymal Stromal Cells for the Treatment of Allograft Rejection After Renal Transplantation”

From Stem Cells Translational Medicine

New means of improving for long-term survival of transplanted kidneys have been searched for unsuccessfully (Pascual et al), but mesenchymal stromal cells (MSCs), which have anti-inflammatory and antifibrotic properties (Franquesa et al, Ninichuk et al and Tolar et al) and prevent renal injury in preclinical models (Casiraghi et al, Ge et al, Inoue et al and Morigi et al) may constitute a new therapeutic option. A relative lack of information (Perico et al and Tan et al), led the group of Ton J. Rabelink at Leiden University Medical Center, Netherlands, in a study published in Stem Cells Translational Medicine, to perform a safety and feasibility study in kidney allograft recipients receiving intravenous infusions of autologous bone marrow (BM) MSCs. Overall they report that this is clinically feasible and safe, and the findings are suggestive of systemic immunosuppression (Reinders et al).

"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).

"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).

"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.

"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.

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).

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).

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).

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).