Combinatorial conditioning of adipose derived-mesenchymal stem cells enhances their neurovascular potential: Implications for intervertebral disc degeneration.

Background: Mesenchymal stem cells (MSCs) are becoming an increasingly attractive option for regenerative therapies due to their availability, self-renewal capacity, multilineage potential, and anti-inflammatory properties. Clinical trials are underway to test the efficacy of stem cell-based therapies for the repair and regeneration of the degenerate intervertebral disc (IVD), a major cause of back pain. Recently, both bone marrow-derived MSCs and adipose-derived stem cells (ASCs) have been assessed for IVD therapy but there is a lack of knowledge surrounding the optimal cell source and the response of transplanted cells to the low oxygen, pro-inflammatory niche of the degenerate disc.

Hypoxia Activates the PTHrP -MEF2C Pathway to Attenuate Hypertrophy in Mesenchymal Stem Cell Derived Cartilage.

Articular cartilage lacks an intrinsic repair capacity and due to the ability of mesenchymal stem cells (MSCs) to differentiate into chondrocytes, MSCs have been touted as a cellular source to regenerate damaged cartilage. However, a number of prevailing concerns for such a treatment remain. Generally, administration of MSCs into a cartilage defect results in poor regeneration of the damaged cartilage with the repaired cartilage consisting primarily of fibro-cartilage rather than hyaline cartilage.

Application of biomaterials to in vitro pluripotent stem cell disease modeling of the skeletal system.

Disease-specific pluripotent stem cells can be derived through genetic manipulation of embryonic stem cells or by reprogramming somatic cells (induced pluripotent stem cells). These cells are a valuable tool to study human diseases in vitro in order to dissect their pathomechanisms and develop novel therapeutics. Although pluripotent stem cell-derived models have successfully recapitulated the abnormalities of some skeletal diseases in vitro, this field is still at its early stages, and it could greatly benefit from the direct application of biomaterial research.

Thermoresponsive Substrates Used for the Growth and Controlled Differentiation of Human Mesenchymal Stem Cells.

This communication outlines the advances made in the development of thermoresponsive substrates for human mesenchymal stem cell (hMSC) expansion and subsequent controlled specific and multilineage differentiation from a previous study performed by this group. Previously, the development of an inexpensive and technically accessible method for hMSC expansion and harvesting was reported, using the solvent casting deposition method and thermoresponsive poly(N-isopropylacrylamide). Here, the logical continuation of this work is reported with the multipassage expansion of hMSCs with phenotypic maintenance followed by induced adipogenic, osteogenic, and chondrogenic differentiation.

ROCK activity and the Gβγ complex mediate chemotactic migration of mouse bone marrow-derived stromal cells.

Introduction: Bone marrow-derived stromal cells (BMSCs), also known as mesenchymal stem cells, are the focus of intensive efforts worldwide to elucidate their function and biology. Despite the importance of BMSC migration for their potential therapeutic uses, the mechanisms and signalling governing stem cell migration are still not fully elucidated.

Methods: We investigated and detailed the effects of MCP-1 activation on BMSCs by using inhibitors of G protein-coupled receptor alpha beta (GPCR αβ), ROCK (Rho-associated, coiled-coil containing protein kinase), and PI3 kinase (PI3K).

Bone Marrow-Derived Mesenchymal Stem Cells Have Innate Procoagulant Activity and Cause Microvascular Obstruction Following Intracoronary Delivery: Amelioration by Antithrombin Therapy.

Mesenchymal stem cells (MSCs) are currently under investigation as tools to preserve cardiac structure and function following acute myocardial infarction (AMI). However, concerns have emerged regarding safety of acute intracoronary (IC) MSC delivery. This study aimed to characterize innate prothrombotic activity of MSC and identify means of its mitigation toward safe and efficacious therapeutic IC MSC delivery post-AMI.

A chondromimetic microsphere for in situ spatially controlled chondrogenic differentiation of human mesenchymal stem cells.

Human mesenchymal stem cells (hMSCs) have been identified as a viable cell source for cartilage tissue engineering. However, to undergo chondrogenic differentiation hMSCs require growth factors, in particular members of the transforming growth factor beta (TGF-β) family. While in vitro differentiation is feasible through continuous supplementation of TGF-β3, mechanisms to control and drive hMSCs down the chondrogenic lineage in their native microenvironment remain a significant challenge.

Impact of mesenchymal stem cell secreted PAI-1 on colon cancer cell migration and proliferation.

Mesenchymal Stem Cells are known to engraft and integrate into the architecture of colorectal tumours, with little known regarding their fate following engraftment. This study aimed to investigate mediators of Mesenchymal Stem Cell (MSC) and colon cancer cell (CCC) interactions. Mesenchymal Stem Cells and colon cancer cells (HT29 and HCT-116) were cultured individually or in co-culture on 3-dimensional scaffolds.

Thermoresponsive substrates used for the expansion of human mesenchymal stem cells and the preservation of immunophenotype.

The facile regeneration of undifferentiated human mesenchymal stem cells (hMSCs) from thermoresponsive surfaces facilitates the collection of stem cells avoiding the use of animal derived cell detachment agents commonly used in cell culture. This communication proposes a procedure to fabricate coatings from commercially available pNIPAm which is both affordable and a significant simplification on alternative approaches used elsewhere. Solvent casting was used to produce films in the micrometer range and successful cell adhesion and proliferation was highly dependent on the thickness of the coating produced with 1 μm thick coatings supporting cells to confluence.

High levels of ephrinB2 over-expression increases the osteogenic differentiation of human mesenchymal stem cells and promotes enhanced cell mediated mineralisation in a polyethyleneimine-ephrinB2 gene-activated matrix.

Gene therapy can be combined with tissue engineering constructs to produce gene-activated matrices (GAMs) with enhanced capacity for repair. Polyethyleneimine (PEI), a non-viral vector, has previously been optimised for high efficiency gene transfer in rat mesenchymal stem cells (rMSCs). The use of PEI to transfect human MSCs (hMSCs) with ephrinB2 is assessed here.

Doxorubicin induces the DNA damage response in cultured human mesenchymal stem cells.

Anthracyclines, including doxorubicin, are widely used in the treatment of leukemia. While the effects of doxorubicin on hematopoietic cells have been characterized, less is known about the response of human mesenchymal stem cells (hMSCs) in the bone marrow stroma to anthracyclines. We characterized the effect of doxorubicin on key DNA damage responses in hMSCs, and compared doxorubicin sensitivity and DNA damage response activation between isolated hMSCs and the chronic myelogenous leukemia cell line, K562.

The electrical stimulation of carbon nanotubes to provide a cardiomimetic cue to MSCs.

Once damaged, cardiac muscle has little intrinsic repair capability due to the poor regeneration potential of remaining cardiomyocytes. One method of overcoming this issue is to deliver functional cells to the injured myocardium to promote repair. To address this limitation we sought to test the hypothesis that electroactive carbon nanotubes (CNT) could be employed to direct mesenchymal stem cell (MSC) differentiation towards a cardiomyocyte lineage.

Development of a thermoresponsive chitosan gel combined with human mesenchymal stem cells and desferrioxamine as a multimodal pro-angiogenic therapeutic for the treatment of critical limb ischaemia.

Critical limb ischaemia (CLI) is a debilitating ischaemic disease caused by vascular occlusion. Pro-angiogenic therapeutics have the potential to produce collateral vasculature, delaying or negating the need for amputation or invasive revascularisation. Thermoresponsive hydrogels can provide an in situ depot for the sustained release of drugs and provide protection and cohesion for encapsulated cells.

Kinetics of thermally induced heat shock protein 27 and 70 expression by bone marrow-derived mesenchymal stem cells.

Although bone marrow-derived mesenchymal stem cells (MSCs) are an attractive cell therapy candidate, their potential is limited by poor survival following transplantation. Over-expression of anti-apoptotic heat shock proteins using viral vectors can improve the survival of these cells under stressful conditions in vitro and in vivo. It is also possible to induce heat shock protein expression in many cell types by simply exposing them to a transient, nonlethal elevation in temperature.

Advancing regenerative surgery in orthopaedic sports medicine: the critical role of the surgeon.

The constant desire to improve outcomes in orthopaedic sports medicine requires us to continuously consider the challenges faced in the surgical repair or reconstruction of soft tissue and cartilaginous injury. In many cases, surgical efforts targeted at restoring normal anatomy and functional status are ultimately impaired by the biological aspect of the natural history of these injuries, which acts as an obstacle to a satisfactory repair process after surgery. The clinical management of sports injuries and the delivery of appropriate surgical intervention are continuously evolving, and it is likely that the principles of regenerative medicine will have an increasing effect in this specialized field of orthopaedic practice going forward.

Activation of DNA damage response pathways in human mesenchymal stem cells exposed to cisplatin or γ-irradiation.

DNA damaging agents are widely used in treatment of hematogical malignancies and solid tumors. While effects on hematopoietic stem cells have been characterized, less is known about the DNA damage response in human mesenchymal stem cells (hMSCs) in the bone marrow stroma, progenitors of osteoblasts, chondrocytes and adipocytes. To elucidate the response of undifferentiated hMSCs to γ-irradiation and cisplatin, key DNA damage responses have been characterised in hMSCs from normal adult donors.

In vitro characterization of an electroactive carbon-nanotube-based nanofiber scaffold for tissue engineering.

In an effort to reduce organ replacement and enhance tissue repair, there has been a tremendous effort to create biomechanically optimized scaffolds for tissue engineering applications. In contrast, the development and characterization of electroactive scaffolds has attracted little attention. Consequently, the creation and characterization of a carbon nanotube based poly(lactic acid) nanofiber scaffold is described herein.

Mesenchymal stem cell inhibition of T-helper 17 cell- differentiation is triggered by cell-cell contact and mediated by prostaglandin E2 via the EP4 receptor.

Mesenchymal stem cells (MSCs) inhibit T-cell activation and proliferation but their effects on individual T-cell-effector pathways and on memory versus naïve T cells remain unclear. MSC influence on the differentiation of naïve and memory CD4(+) T cells toward the Th17 phenotype was examined. CD4(+) T cells exposed to Th17-skewing conditions exhibited reduced CD25 and IL-17A expression following MSC co-culture.

Mesenchymal Stem Cell-mediated delivery of the sodium iodide symporter supports radionuclide imaging and treatment of breast cancer.

Mesenchymal Stem Cells (MSCs) migrate specifically to tumors in vivo, and coupled with their capacity to bypass immune surveillance, are attractive vehicles for tumor-targeted delivery of therapeutic agents. This study aimed to introduce MSC-mediated expression of the sodium iodide symporter (NIS) for imaging and therapy of breast cancer. Tumor bearing animals received an intravenous or intratumoral injection of NIS expressing MSCs (MSC-NIS), followed by (99m) Technetium pertechnetate imaging 3-14 days later using a BazookaSPECT γ-camera.

Mesenchymal chondroprogenitor cell origin and therapeutic potential.

Mesenchymal progenitor cells, a multipotent adult stem cell population, have the ability to differentiate into cells of connective tissue lineages, including fat, cartilage, bone and muscle, and therefore generate a great deal of interest for their potential use in regenerative medicine. During development, endochondral bone is formed from a template of cartilage that transforms into bone; however, mature articular cartilage remains in the articulating joints, where its principal role is reducing friction and dispersing mechanical load. Articular cartilage is prone to damage from sports injuries or ageing, which regularly progresses to more serious joint disorders, such as osteoarthritis.

Potential of rat bone marrow-derived mesenchymal stem cells as vehicles for delivery of neurotrophins to the Parkinsonian rat brain.

Issues related to the intra-cerebral delivery of glial cell line-derived neurotrophic factor (GDNF) have hampered its progression as a neuroprotective therapy for Parkinson's disease. Ex vivo gene therapy, where cells are virally transduced in vitro to produce a specific protein, may circumvent some of the problems associated with direct delivery of this neurotrophin to the brain. In this regard, bone marrow-derived mesenchymal stem cells (MSCs) offer an ideal cell source for ex vivo gene therapy because they are easily isolated from autologous sources, they are amenable to viral transduction and expansion in vitro, and they are hypoimmunogenic and non-tumourigenic in the brain.

Mesenchymal stem cells and osteoarthritis: remedy or accomplice?

Multipotent mesenchymal stromal or stem cells (MSCs) are likely to be agents of connective tissue homeostasis and repair. Because the hallmark of osteoarthritis (OA) is degeneration and failure to repair connective tissues it is compelling to think that these cells have a role to play in OA. Indeed, MSCs have been implicated in the pathogenesis of OA and, in turn, progression of the disease has been shown to be therapeutically modulated by MSCs.