During the past several years, there has been intense research in the field of bone marrow-derived stem cell (BMSC) therapy to facilitate its translation into clinical setting. Although a lot has been accomplished, plenty of challenges lie ahead. Furthermore, there is a growing body of evidence showing that administration of BMSC-derived conditioned media (BMSC-CM) can recapitulate the beneficial effects observed after stem cell therapy. BMSCs produce a wide range of cytokines and chemokines that have, until now, shown extensive therapeutic potential. These paracrine mechanisms could be as diverse as stimulating receptor-mediated survival pathways, inducing stem cell homing and differentiation or regulating the anti-inflammatory effects in wounded areas. The current review reflects the rapid shift of interest from BMSC to BMSC-CM to alleviate many logistical and technical issues regarding cell therapy and evaluates its future potential as an effective regenerative therapy.

Tom J. Burdon

Arghya Paul

Nicolas Noiseux

Satya Prakash

Dominique Shum-Tim

Bone Marrow Stem Cell Derived Paracrine Factors for Regenerative Medicine: Current Perspectives and Therapeutic Potential

Congenital bone marrow failure syndromes (BMFSs) are relatively rare disorders characterized by aberrant development in one or more hematopoietic lineages.  Genetic alterations have now been identified in most of these disorders although the exact role of the molecular defects has yet to be elucidated.  Most of these diseases are successfully managed with supportive care, however, treatment refractoriness and disease progression—often involving malignant transformation—may necessitate curative treatment with hematopoietic stem cell transplantation.  Due to the underlying molecular defects, the outcome of transplantation for BMFS may be dramatically different than those associated with transplantation for more common diseases, including leukemia.  Given recent improvements in survival and molecular diagnosis of bone marrow failure syndrome patients presenting at adult ages without physical stigmata, it is important for both pediatric and adult hematologists to be aware of the possible diagnosis of BMF syndromes and the unique approaches required in treating such patients.

Kenji Morimoto

Theodore B. Moore

Gary Schiller

Kathleen M. Sakamoto

Transplantation for Congenital Bone Marrow Failure Syndromes

The human Notch system consists of 5 ligands and 4 membrane receptors with promiscuous ligand binding, and Notch-initiated signalling interacts with a wide range of other intracellular  pathways. The receptor signalling seems important for regulation of normal and malignant hematopoiesis, development of the cellular immune system, and regulation of immune responses. Several Notch-targeting agents are now being developed, including natural receptor ligands, agonistic and antagonistic antibodies, and inhibitors of intracellular Notch-initiated signalling. Some of these agents are in clinical trials, and several therapeutic strategies seem possible in stem cell recipients: (i) agonists may be used for stem cell expansion and possibly to enhance posttransplant lymphoid reconstitution; (ii) receptor-specific agonists or antagonists can be used for immunomodulation; (iii) Notch targeting may have direct anticancer effects. Although the effects of therapeutic targeting are difficult to predict due to promiscuous ligand binding, targeting of this system may represent an opportunity to achieve combined effects with earlier posttransplant reconstitution, immunomodulation, or direct anticancer effects.

Elisabeth Ersvaer

Kimberley J. Hatfield

Håkon Reikvam

Øystein Bruserud

Future Perspectives: Therapeutic Targeting of Notch Signalling May Become a Strategy in Patients Receiving Stem Cell Transplantation for Hematologic Malignancies

Acute Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation. Although this process is thought to consist of several phases, T-cell activation plays a critical role in the pathogenesis of acute GVHD. To become efficient effectors, T-cells require additional costimulation after T-cell receptor signaling. A number of molecules are involved in costimulation of T-cells such as CD28, CD40L, CD30, OX40, 4-1BB, ICOS, and LIGHT. The system is regulated by inhibitory molecules, CTLA-4, and PD-1. There is experimental evidence that those molecules are implicated in the pathogenesis of GHVD. We describe how these molecules are involved in acute GVHD and how the blockade of costimulatory molecules may have potential implications for the treatment of patients with acute GVHD.

Javier Briones

Silvana Novelli

Jorge Sierra

T-Cell Costimulatory Molecules in Acute-Graft-Versus Host Disease: Therapeutic Implications

Background. Hyperbaric oxygen (HBO) therapy, which is used for many conditions, may also have immunosuppressive effects and could be used for prevention or treatment of graft-versus-host disease (GvHD). If HBO is immunosuppressant, then we hypothesize that HBO therapy will delay the T-cell mediated skin graft rejection. Methods. C57/BL6 black-coated (H2B) mice received skin graft from CBA (H2D) white-coated mice. Mice were treated with either 19 session of 240 kpa oxygen or 29 session of 300 kpa oxygen, for 90 minutes. Mice were housed either 4 per cage or separately, to prevent friction and mechanical factors that may affect graft survival. Skin grafts were assessed daily. Results. There was no difference in length of graft survival between mice that received either regimens of HBO therapy and mice that did not receive HBO therapy. Conclusions. HBO therapy, as a sole agent, did not delay skin graft rejection in a highly immunogenic mouse model.

Adam Gassas

Weixian Min

A. Wayne Evans

Susan Carter

George K. Sándor

Eyal Grunebaum

Hyperbaric Oxygen Therapy as a Sole Agent Is Not Immunosuppressant in a Highly Immunogenic Mouse Model

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Bone Marrow Research