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"Pittenger, Mark"
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Mesenchymal stem cell perspective: cell biology to clinical progress
The terms MSC and MSCs have become the preferred acronym to describe a cell and a cell population of multipotential stem/progenitor cells commonly referred to as mesenchymal stem cells, multipotential stromal cells, mesenchymal stromal cells, and mesenchymal progenitor cells. The MSCs can differentiate to important lineages under defined conditions in vitro and in limited situations after implantation in vivo. MSCs were isolated and described about 30 years ago and now there are over 55,000 publications on MSCs readily available. Here, we have focused on human MSCs whenever possible. The MSCs have broad anti-inflammatory and immune-modulatory properties. At present, these provide the greatest focus of human MSCs in clinical testing; however, the properties of cultured MSCs in vitro suggest they can have broader applications. The medical utility of MSCs continues to be investigated in over 950 clinical trials. There has been much progress in understanding MSCs over the years, and there is a strong foundation for future scientific research and clinical applications, but also some important questions remain to be answered. Developing further methods to understand and unlock MSC potential through intracellular and intercellular signaling, biomedical engineering, delivery methods and patient selection should all provide substantial advancements in the coming years and greater clinical opportunities. The expansive and growing field of MSC research is teaching us basic human cell biology as well as how to use this type of cell for cellular therapy in a variety of clinical settings, and while much promise is evident, careful new work is still needed.
Journal Article
Multilineage Potential of Adult Human Mesenchymal Stem Cells
Human mesenchymal stem cells are thought to be multipotent cells, which are present in adult marrow, that can replicate as undifferentiated cells and that have the potential to differentiate to lineages of mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Cells that have the characteristics of human mesenchymal stem cells were isolated from marrow aspirates of volunteer donors. These cells displayed a stable phenotype and remained as a monolayer in vitro. These adult stem cells could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages. Individual stem cells were identified that, when expanded to colonies, retained their multilineage potential.
Journal Article
MSC Pretreatment for Improved Transplantation Viability Results in Improved Ventricular Function in Infarcted Hearts
Many clinical studies utilizing MSCs (mesenchymal stem cells, mesenchymal stromal cells, or multipotential stromal cells) are underway in multiple clinical settings; however, the ideal approach to prepare these cells in vitro and to deliver them to injury sites in vivo with maximal effectiveness remains a challenge. Here, pretreating MSCs with agents that block the apoptotic pathways were compared with untreated MSCs. The treatment effects were evaluated in the myocardial infarct setting following direct injection, and physiological parameters were examined at 4 weeks post-infarct in a rat permanent ligation model. The prosurvival treated MSCs were detected in the hearts in greater abundance at 1 week and 4 weeks than the untreated MSCs. The untreated MSCs improved ejection fraction in infarcted hearts from 61% to 77% and the prosurvival treated MSCs further improved ejection fraction to 83% of normal. The untreated MSCs improved fractional shortening in the infarcted heart from 52% to 68%, and the prosurvival treated MSCs further improved fractional shortening to 77% of normal. Further improvements in survival of the MSC dose seems possible. Thus, pretreating MSCs for improved in vivo survival has implications for MSC-based cardiac therapies and in other indications where improved cell survival may improve effectiveness.
Journal Article
Human Mesenchymal Stem Cells Maintain Transgene Expression during Expansion and Differentiation
Human adult bone marrow contains both hematopoietic stem cells that generate cells of all hematopoietic lineages and human mesenchymal stem cells (hMSCs), which support hematopoiesis and contribute to the regeneration of multiple connective tissues. The goal of the current study was to demonstrate that transduced hMSCs maintain transgene expression after stem cell differentiation in vitro and in vivo. We have introduced genes into cultured hMSCs by retroviral vector transfer and demonstrated long-term in vitro and in vivo expression of human interleukin 3 (hIL-3) and green fluorescent protein (GFP). Protocols were developed to achieve transduction efficiencies of 80–90% in these stem cells. In vitro expression of hIL-3 averaged 350 ng/106cells/24 h over 17 passages (>6 months) and GFP expression was stable over the same time period. Transduced hMSCs were able to differentiate into osteogenic, adipogenic, and chondrogenic lineages and maintained transgene expression after differentiation. Parallel studies were performed in vivo using NOD/SCID mice. Human MSCs expressing hIL-3 were cultured on several matrices and then delivered by subcutaneous, intravenous, and intraperitoneal routes. Sampling of peripheral blood demonstrated that systemic hIL-3 expression was maintained in the range of 100–800 pg/ml over a period of 3 months. These results illustrate the ability of hMSCs to express genes of therapeutic potential and demonstrate their potential clinical utility as cellular vehicles for systemic gene delivery.
Journal Article
Class Unknown
Since the Gilded Age, social scientists, middle-class reformers,
and writers have left the comforts of their offices to \"pass\" as
steel workers, coal miners, assembly-line laborers, waitresses,
hoboes, and other working and poor people in an attempt to gain a
fuller and more authentic understanding of the lives of the working
class and the poor. In this first, sweeping study of undercover
investigations of work and poverty in America, award-winning
historian Mark Pittenger examines how intellectuals were shaped by
their experiences with the poor, and how despite their sympathy
toward working-class people, they unintentionally helped to develop
the contemporary concept of a degraded and \"other\" American
underclass. While contributing to our understanding of the history
of American social thought, Class Unknown offers a new perspective
on contemporary debates over how we understand and represent our
own society and its class divisions.
eBook
MSCs: Scientific Support for Multiple Therapies
[...]a typical clinical dose of MSCs is 100 million cells in 30-50 mL, which is approximately 400 uL of packed cells. There are several reasons for this approach including the following: (1) MSCs secrete powerful anti-inflammatory factors and all tissue injury is accompanied by inflammation; (2) MSCs produce angiogenic factors and interaction with other cell types further enhances their production of these factors, which are needed during tissue repair; (3) MSCs become adapted to in vitro metabolic conditions; and (4) most MSCs do not survive the quick transition to in vivo conditions. [...]the field still needs reliable measures of cell survival and engraftment both short term and long term following administration to patients.
Journal Article
Pim-1 Kinase Cooperates with Serum Signals Supporting Mesenchymal Stem Cell Propagation
Mesenchymal stem cells (MSCs) are currently undergoing testing in several clinical settings. The propagation of MSCs from multiple species in culture is an important step in furthering our understanding of these progenitor cells. Pim-1, a proto-oncogenic serine/threonine kinase, regulates cell proliferation, survival, and differentiation. Although it has been shown that Pim-1 participates in signal transduction mediating mitogenic action in MSCs, its roles in the modulation of MSC propagation remain to be defined. Understanding of ovine MSCs transduced with Pim-1 may provide improved ovine models for cellular therapy development. Using genetically modified ovine MSCs that constitutively overexpressed Pim-1 (MSC expressing PIM-1 and ZsGreen protein), we evaluated the impact of elevated Pim-1 activity on the proliferation, survival, and differentiation of MSCs in culture. Our results showed that Pim-1 enhanced the intrinsic molecular signals of growth and survival implicated in the mediation of serum signaling under normal culture conditions (10% serum). We found that Pim-1 promoted MSC proliferation irrespectively of the serum concentration, but with a decreased proliferation rate compared to increased serum concentrations, relative to the control vector-transduced MSC expressing ZsGreen protein. Further, Pim-1 prevented MSC apoptosis induced by hypoxia or serum deprivation as evidenced by enhanced mitochondria integrity and reduced annexin V binding. Interestingly, the phenotype and multilineage differentiation potential of the cells were not influenced by Pim-1. Taken together, these observations demonstrate that Pim-1 kinase cooperates with exogenous serum signals supporting MSC propagation in the ovine model.
Journal Article
Mesenchymal Stem Cell Transplantation Improves Regional Cardiac Remodeling Following Ovine Infarction
Progressive cardiac remodeling, including the myopathic process in the adjacent zone following myocardial infarction (MI), contributes greatly to the development of cardiac failure. Cardiomyoplasty using bone marrow‐derived mesenchymal stem cells (MSCs) has been demonstrated to protect cardiomyocytes and/or repair damaged myocardium, leading to improved cardiac performance, but the therapeutic effects on cardiac remodeling are still under investigation. Here, we tested the hypothesis that MSCs could improve the pathological remodeling of the adjacent myocardium abutting the infarct. Allogeneic ovine MSCs were transplanted into the adjacent zone by intracardiac injection 4 hours after infarction. Results showed that remodeling and contractile strain alteration were reduced in the adjacent zone of the MSC‐treated group. Cardiomyocyte hypertrophy was significantly attenuated with the normalization of the hypertrophy‐related signaling proteins phosphatidylinositol 3‐kinase α (PI3Kα), PI3Kγ, extracellular signal‐regulated kinase (ERK), and phosphorylated ERK (p‐ERK) in the adjacent zone of the MSC‐treated group versus the MI‐alone group. Moreover, the imbalance of the calcium‐handling proteins sarcoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA2a), phospholamban (PLB), and sodium/calcium exchanger type 1 (NCX‐1) induced by MI was prevented by MSC transplantation, and more strikingly, the activity of SERCA2a and uptake of calcium were improved. In addition, the upregulation of the proapoptotic protein Bcl‐xL/Bcl‐2‐associated death promoter (BAD) was normalized, as was phospho‐Akt expression; there was less fibrosis, as revealed by staining for collagen; and the apoptosis of cardiomyocytes was significantly inhibited in the adjacent zone by MSC transplantation. Collectively, these data demonstrate that MSC implantation improved the remodeling in the region adjacent to the infarct after cardiac infarction in the ovine infarction model. This study tested the hypothesis that mesenchymal stem cells (MSCs) could improve pathological remodeling of the adjacent myocardium abutting the infarct after myocardial infarction. Allogeneic ovine MSCs were transplanted into the adjacent zone by intracardiac injection 4 hours after infarction. Results showed that remodeling and contractile strain alteration were improved in the adjacent zone of the MSC‐treated group.
Journal Article