Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal stem cells that can be isolated from many adult tissues. They can differentiate into cells of the mesodermal lineage, such as adipocytes, osteocytes and chondrocytes, as well as cells of other embryonic lineages. MSCs can interact with cells of both the innate and adaptive immune systems, leading to the modulation of several effector functions. After in vivo administration, MSCs induce peripheral tolerance and migrate to injured tissues, where they can inhibit the release of pro-inflammatory cytokines and promote the survival of damaged cells. This Review discusses the targets and mechanisms of MSC-mediated immunomodulation and the possible translation of MSCs to new therapeutic approaches.

Mesenchymal stem cells in health and disease

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(08)60690-X.pdf

Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study.

MSCs are nonhematopoietic stromal cells that are capable of differentiating into, and contribute to the regeneration of, mesenchymal tissues such as bone, cartilage, muscle, ligament, tendon, and adipose. MSCs are rare in bone marrow, representing approximately 1 in 10,000 nucleated cells. Although not immortal, they have the ability to expand manyfold in culture while retaining their growth and multilineage potential. MSCs are identified by the expression of many molecules including CD105 (SH2) and CD73 (SH3/4) and are negative for the hematopoietic markers CD34, CD45, and CD14. The properties of MSCs make these cells potentially ideal candidates for tissue engineering. It has been shown that MSCs, when transplanted systemically, are able to migrate to sites of injury in animals, suggesting that MSCs possess migratory capacity. However, the mechanisms underlying the migration of these cells remain unclear. Chemokine receptors and their ligands and adhesion molecules play an important role in tissue-specific homing of leukocytes and have also been implicated in trafficking of hematopoietic precursors into and through tissue. Several studies have reported the functional expression of various chemokine receptors and adhesion molecules on human MSCs. Harnessing the migratory potential of MSCs by modulating their chemokine-chemokine receptor interactions may be a powerful way to increase their ability to correct inherited disorders of mesenchymal tissues or facilitate tissue repair in vivo. The current review describes what is known about MSCs and their capacity to home to tissues together with the associated molecular mechanisms involving chemokine receptors and adhesion molecules.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/epdf/10.1634/stemcells.2007-0197

Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing.

The emerging field of regenerative medicine will require a reliable source of stem cells in addition to biomaterial scaffolds and cytokine growth factors. Adipose tissue represents an abundant and accessible source of adult stem cells with the ability to differentiate along multiple lineage pathways. The isolation, characterization, and preclinical and clinical application of adipose-derived stem cells (ASCs) are reviewed in this article.

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Adipose-Derived Stem Cells for Regenerative Medicine

Immunomodulatory properties of mesenchymal stromal cells.

https://www.exphem.org/article/S0301-472X(01)00769-X/pdf

Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo.

Although allogeneic transplantation can be curative for patients with sickle cell disease, the toxicity of conditioning regimens has precluded its use in adults with significant end-organ damage. Newer conditioning regimens have been developed that are less toxic and that may broaden the applicability of allogeneic transplantation in this disorder. We report two adults with end-stage sickle cell disease, who underwent allogeneic transplantation from an HLA-identical sibling donor after conditioning with fludarabine/melphalan and ATG. Both patients had been extensively transfused and one had multiple RBC antibodies. One of the patients also had end-stage renal disease, and was dialysis dependent. Engraftment occurred promptly in both patients. Both achieved 100% donor chimerism and both were free of pain crises after transplant. The first patient died of a respiratory failure related to chronic graft-versus-host disease (GVHD) on day 335 after transplantation. The second patient developed severe gastro-intestinal GVHD and TTP and died on day 147 after transplantation. Conditioning with fludarabine/melphalan and ATG followed by allogeneic stem cell transplantation resulted in prompt and reliable engraftment in adults with end-stage sickle cell disease. The incidence of severe GVHD was unacceptably high and may be related to the ethnicity of the patients or to the inflammatory state associated with pre-existing sickle cell disease.

Fludarabine-based conditioning for allogeneic transplantation in adults with sickle cell disease.

Allogeneic stem cell transplantation is increasingly considered as a curative though risky treatment option for adults with sickle cell disease. Little is known about attitudes of adult patients and their health care providers regarding the risks and benefits of transplantation. A survey of 100 patients and their health care providers was undertaken. Assessment of risk was by a reference gamble paradigm. Comparison was made of the characteristics of those accepting substantial risk vs those not accepting risk, as well as assessment of agreement on risks recommended by health care providers and accepted by patients. Sixty-three of 100 patients were willing to accept some short-term risk of mortality in exchange for the certainty of cure. Fifteen patients were willing to accept more than 35% mortality risk. No differences in patient or disease-related variables were identified between those accepting risk and those not accepting risk. There was no agreement between the recommendations of health care providers and the risk accepted by patients. A substantial proportion of adults with sickle cell disease are interested in curative treatment, at the expense of considerable risk. The decision to accept risk is influenced by individual patient values that cannot be easily quantified and that do not correlate with the assessment of the health care provider. Given the substantial interest in curative therapy, education about and consultation for allogeneic stem cell transplantation in sickle cell patients should be encouraged.

Allogeneic stem cell transplantation for sickle cell disease. A study of patients' decisions.

Autologous and allogeneic transplantation are increasingly used in the management of patients with chronic lymphocytic leukemia. Many questions regarding patient selection, efficacy and outcome are unresolved, hence a review of the literature through Medline search. Autologous transplantation for CLL has been used mainly in selected patients under the age of 60. Conditioning typically involves total body irradiation (TBI). Bone marrow and more recently peripheral blood stem cells are used. Treatment-related mortality in most series is less than 10%. Molecular remissions after autologous transplantation are common, and clinical remissions can be prolonged in some patients. Randomized studies are needed to establish whether autologous transplantation confers a survival benefit over standard chemotherapy approaches. Allogeneic transplantation has a considerable treatment-related mortality, but durable remissions sometimes occur in patients with advanced disease. The use of non-myeloablative 'mini-transplants' has been investigated as a method to reduce treatment-related mortality, but prolonged follow-up will be required to establish the cure rate obtained with this procedure. Autologous and allogeneic transplantation are promising treatment modalities. Further refinements of transplant techniques and properly designed prospective studies are necessary to establish the role of stem cell transplantation in the overall management of CLL.

Allogeneic and autologous transplantation for chronic lymphocytic leukemia.

A total of 31 consecutive patients with hematologic malignancies who were considered poor candidates for TBI underwent allogeneic stem cell transplantation after conditioning with fludarabine and melphalan. A total of 25 matched sibling recipients received fludarabine 25 mg/m(2) x 5 days and melphalan 70 mg/m(2) x 2 days. For unrelated and haploidentical donor recipients, fludarabine was increased to 30 mg/m(2) and ATG 30 mg/kg x 4 days was added. Graft-versus-host disease prophylaxis consisted of tacrolimus and mini methotrexate. All patients engrafted. Regimen-related toxicity was considerable and included mainly renal, hepatic and mucosal toxicity. There were seven regimen-related-deaths including two VOD, two pulmonary, one renal, one cardiac and one mucosal toxicity. One case of fatal pulmonary toxicity death could be attributed to pre-existing pulmonary damage. Progression-free survival at 12 months was 44% (90% CI: 30-58%) for recipients of HLA-identical sibling transplants and 33% (90% CI: 21-45%) for all patients. In conclusion, the fludarabine-melphalan regimen leads to consistent engraftment. The regimen-related toxicity is considerable and cannot be explained solely by patient selection. Cardiac toxicity is emerging as a unique toxicity of this regimen. Despite toxicity, fludarabine-melphalan has considerable activity and leads to durable remission in a proportion of patients.

S. Devine

Papers

Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo.

Fludarabine-based conditioning for allogeneic transplantation in adults with sickle cell disease.

Allogeneic stem cell transplantation for sickle cell disease. A study of patients' decisions.

Allogeneic and autologous transplantation for chronic lymphocytic leukemia.

Regimen-related toxicity after fludarabine-melphalan conditioning: a prospective study of 31 patients with hematologic malignancies.