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Dudley B.,Case Western Reserve University | Palumbo C.,University of Toledo | Nalepka J.,Athersys, Inc. | Molyneaux K.,Case Western Reserve University
Developmental Biology | Year: 2010

Stem cells are necessary to maintain tissue homeostasis and the microenvironment (a.k.a. the niche) surrounding these cells controls their ability to self-renew or differentiate. For many stem cell populations it remains unclear precisely what cells and signals comprise a niche. Here we identify a possible PGC niche in the mouse genital ridges. Conditional ablation of Bmpr1a was used to demonstrate that BMP signaling is required for PGC survival and migration as these cells colonize the genital ridges. Reduced BMP signaling within the genital ridges led to increased somatic cell death within the mesonephric mesenchyme. Loss of these supporting cells correlated with decreased levels of the mesonephric marker, Pax2, as well as a reduction in genes expressed in the coelomic epithelium including the putative PGC chemo-attractants Kitl and Sdf1a. We propose that BMP signaling promotes mesonephric cell survival within the genital ridges and that these cells support correct development of the coelomic epithelium, the target of PGC migration. Loss of BMP signaling leads to the loss of the PGC target resulting in reduced PGC numbers and disrupted PGC migration. © 2010 Elsevier Inc. Source

Auletta J.J.,Seidman Cancer Center | Auletta J.J.,Case Western Reserve University | Deans R.J.,Case Western Reserve University | Deans R.J.,Athersys, Inc. | Bartholomew A.M.,University of Illinois at Chicago
Blood | Year: 2012

Multipotent, bone marrow-derived stromal cells (BMSCs, also known as mesenchymal stem cells [MSCs]), are cultureexpanded, nonhematopoietic cells with immunomodulatory effects currently being investigated as novel cellular therapy to prevent and to treat clinical disease associated with aberrant immune response. Emerging preclinical studies suggest that BMSCs may protect against infectious challenge either by direct effects on the pathogen or through indirect effects on the host. BMSCs may reduce pathogen burden by inhibiting growth through soluble factors or by enhancing immune cell antimicrobial function. In the host, BMSCs may attenuate pro-inflammatory cytokine and chemokine induction, reduce pro-inflammatory cell migration into sites of injury and infection, and induce immunoregulatory soluble and cellular factors to preserve organ function. These preclinical studies provide provocative hints into the direction MSC therapeutics may take in the future. Notably, BMSCs appear to function as a critical fulcrum, providing balance by promoting pathogen clearance during the initial inflammatory response while suppressing inflammation to preserve host integrity and facilitate tissue repair. Such exquisite balance in BMSC function appears intrinsically linked to Toll-like receptor signaling and immune crosstalk. © 2012 by The American Society of Hematology. Source

Viswanathan S.,A+ Network | Keating A.,A+ Network | Deans R.,Athersys, Inc. | Hematti P.,University of Wisconsin - Madison | And 6 more authors.
Stem Cells and Development | Year: 2014

The mesenchymal stromal cell (MSC) field continues to rapidly progress with a number of clinical trials initiated and completed, with some reported successes in multiple clinical indications, and a growing number of companies established. The field, nevertheless, faces several challenges. Persistent issues include the definition of a MSC and comparability between MSC preparations. This is because of inherent cell heterogeneity, the absence of markers that are unique to MSCs, and the difficulty in precisely defining them by developmental origin. Differences in the properties of MSCs also depend on the site of tissue harvest, phenotypic and genotypic characteristics of the donor and the isolation, and storage and expansion methods used. These differences may be sufficient to ensure that attributes of the final MSC product could differ in potentially significant ways. Since there are currently no gold standards, we propose using a reference material to establish methods of comparability among MSC preparations. We suggest four possible "ruler scenarios" and a method for global distribution. We further suggest that critical to establishing a reference material is the need to define protocols for comparing cells. The main purpose of this article is to solicit input in establishing a consensus-based comparison. A comparative approach will be critical to all stages of translation to better clarify mechanisms of MSC actions, define an optimal cell manufacturing process, ensure best practice clinical investigations, extend the use of an MSC product for new indications, protect an MSC product from imitators, and develop uniform reimbursement policies. Importantly, a reference material may enable a consensus on a practical definition of MSCs. © Copyright 2014, Mary Ann Liebert, Inc. Source

Newell L.F.,Oregon Health And Science University | Deans R.J.,Athersys, Inc. | Maziarz R.T.,Oregon Health And Science University
Expert Opinion on Biological Therapy | Year: 2014

Introduction: Early reports demonstrated the safety of adherent mesenchymal stromal cell (MSC) infusions in the hematopoietic stem cell transplantation (HCT) setting, as well as clinical efficacy for treatment of steroid refractory acute graft-versus-host disease (GVHD); however, two large, Phase III randomized, placebo-controlled trials of MSC for initial therapy or steroid refractory GVHD failed to meet their primary endpoints of durable complete response. Subset analyses demonstrated efficacy in selected patient populations, contributing to recent approvals of MSC for pediatric patients in Canada and New Zealand. Areas covered: In this review, we discuss the biologic and immunomodulatory properties of MSC and potential mechanisms involved. We review the results of prior clinical trials incorporating MSC for GVHD treatment or prophylaxis, the recent approvals in Canada and New Zealand, as well as future directions in the field. Expert opinion: The role of MSC infusions, in the prophylaxis and/or treatment of GVHD after HCT, continues to be under active investigation. Whether, and how, to incorporate MSC infusions is unclear, and ongoing questions include the source tissue type and culture methods, the timing and dosage of MSC product infusions, as well as the optimal clinical trial design and endpoints for assessment of clinical response. © 2014 Informa UK, Ltd. Source

Ting A.E.,Athersys, Inc. | Sherman W.,Columbia University
Current Opinion in Organ Transplantation | Year: 2012

PURPOSE OF REVIEW: Stem cell therapy for the treatment of cardiovascular disease is rapidly moving from bench to bedside. In the settings of acute and chronic myocardial injury, approaches to treatment have explored various cell populations, delivery methods, and times of administration. RECENT FINDINGS: Although initial studies in patients were performed with unfractionated bone marrow cells, further investigations in animal models of myocardial disease have elucidated mechanisms of benefit and opened doors to treatment strategies with stem cells of varied derivation. SUMMARY: Allogeneic stem cell populations have demonstrated therapeutic promise in ischemic heart disease, without a requirement for immunosuppressive drugs, and offer the potential to create large-scale, cryopreserved banks of cells for 'off the shelf' utility. Copyright © 2012 Lippincott Williams & Wilkins. Source

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