Human umbilical cord mesenchymal stromal cells mitigate chemotherapy-associated tissue injury in a pre-clinical mouse model
Introduction
Myelosuppression and mucositis are commonproblems that cause significant morbidity and occasionally mortalityduring and after chemotherapy 1., 2., 3.). Although chemotherapeuticagents can kill rapidly proliferating tumor cells, these drugs do not differentiate between killing tumor cells and normal cells, thus rapidly dividing normal cells in the bone marrow and gastrointestinal tract are also frequently damaged, causing bone marrow suppression and gastrointestinal injury. Some cytotoxic chemotheraputics can also induce cardiotoxicity, neurotoxicity and nephrotoxicity 3., 4., 5.), severely impacting the quality of life of patients and occasionally limiting the dose of chemotherapy. More than 40% of patients with cancer undergoing chemotherapy develop side-effects (6). With the large numbers of patients being diagnosed with cancer and given the serious concern of quality of life, developing novel therapeutic strategies to alleviate chemotherapy-induced side-effects has recently been the major focus of oncologists. Although recent advances in understanding the underlying mechanisms of myelosuppression and gastrointestinal mucositis in experimental animal models and human patients, until now there has been no effective treatment for the established symptoms.
Mesenchymal stromal cells (MSC) are a subset ofnon-hematopoietic primitive cells originating from the mesodermalgerm layer, and are classically characterized by their ability todifferentiate into cells of mesenchymal tissues, such as bone,cartilage, tendon, ligament, muscle and adipose 7., 8., 9.). Apartfrom their multilineage potential, MSC also constitute an essential hematopoietic stem cell (HSC) niche component, secreting hematopoietic growth factors to enhance HSC mobilization, homing and repopulation (10, 11). Recent studies have shown that systemic administration of MSC facilitates HSC implantation and results in accelerated hematopoietic recovery in experimental animal models and in clinical practice 12., 13., 14., 15.). MSC can also secrete a wide panel of cytokines and immunoregulatory molecules that have pleiotropic effects on a variety of cell types and induce both tissue regeneration and pathologic changes 16., 17., 18., 19.). Meanwhile, studies have demonstrated that MSC can home to damaged intestinal tract and facilitate mucosal repair by enhancing microcirculation and modulating autoimmune responses 20., 21., 22.). These characteristics of MSC make it an excellent reagent to repair chemotherapy-induced tissue injury.
MSC have inherent tumoritropic migratory properties, which makes them ideal delivery vehicles in gene therapy (23, 24). But the interaction between unmodified MSC and tumor remains controversial, some studies reporting that MSC promotes tumor progression and metastasis, while other studies have demonstrated that MSC suppress tumor initiation and growth (25, 26).
In this study, we have verified that human umbilical cord (hUC)-derived MSC, a subset of progenitor cells similar to bone marrow MSC with respect to cell characteristics and multilineage differentiation, can mitigate adriamycin (ADM)-induced side-effects while not impacting tumor progression.
Section snippets
Animals
Female C57BL/6 mice and male athymic Balb/C nude mice (Laboratory Animal Center, Academy of Military Medical Sciences, Beijing, China) aged 6–8 weeks were used for the experiments. The animals received human care and all animal experimental procedures were carried out with the approval of the Animal Use and Care Committee of Beijing Institute of Radiation Medicine (Beijing, China).
hUC MSC preparation and cell culture
hUC samples were obtained from local maternity hospitals with the donors' informed consent, and MSC were isolated
Immunophenotype and differentiation of isolated hUC MSC
MSC cultured at passage 5 were used for characterization by flow cytometry analysis and in vitro osteogenic and adipogenic differentiation. The isolated stromal cells displayed typical MSC surface antigen profiles, with prominent expression of CD29, CD44, CD73 and major histocompatibility complex (MHC) class I (HLA-ABC) and a lack of expression of CD31, CD34, CD45 and MHC class II (HLA-DR). The cell preparations used for the experiments were capable of differentiating into adipocytes when
Discussion
MSC have shown great potential for therapeutic applications for various diseases. These cells can differentiate into different tissues originating from mesoderm-like cartilage, bone and cardiac muscle. Accumulating data show that MSC are also capable of differentiating into cells of non-mesodermic origin, such as neurons and endothelial cells, under appropriate stimuli (28, 29). Furthermore, MSC express low levels of MHC class I surface antigens and do not express MHC class II antigens, and
Acknowledgments
This work was supported by the Wuzuze Foundation for Sci-Tech Development, Beijing, and the Foundation of National Basic Research Program of China (number 2012CB518105, 2010CB833600).
Disclosure of potential conflicts of interest: The authors indicate no potential conflicts of interest.
References (42)
- et al.
Doxorubicin-induced cardiomyopathy: from the cardiotoxic mechanisms to management
Prog Cardiovas Dis
(2007) - et al.
Mesenchymal stem cells promote engraftment of human umbilical cord blood-derived CD34 + cells in NOD/SCID mice
Exp Hematol
(2002) - et al.
Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients
Biol Blood Marrow Transplant
(2005) - et al.
Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation
Blood
(2007) - et al.
Nonmyeloablative stem cell therapy enhances microcirculation and tissue regeneration in murine inflammatory bowel disease
Gastroenterology
(2007) - et al.
Method to isolate mesenchymal-like cells from Wharton's jelly of umbilical cord
Meth Cell Biol
(2008) - et al.
Reconstitution of the functional human hematopoietic microenvironment derived from human mesenchymal stem cells in the murine bone marrow compartment
Blood
(2006) - et al.
Umbilical cord mesenchymal stem cells: adjuvants for human cell transplantation
Biol Blood Marrow Transplant
(2007) - et al.
Cotransplantation of human mesenchymal stem cells enhances human myelopoiesis and megakaryocytopoiesis in NOD/SCID mice
Exp Hematol
(2003) - et al.
Bone marrow is a source of regenerated cardiomyocytes in doxorubicin-induced cardiomyopathy and granulocyte colony-stimulating factor enhances migration of bone marrow cells and attenuates cardiotoxicity of doxorubicin under electron microscopy
J Heart Lung Transplant
(2004)
Mesenchymal stem cells derived from bone marrow favor tumor cell growth in vivo
Exp Mol Pathol
Changing patient perceptions of the side effects of cancer chemotherapy
Cancer
Chemotherapy-induced neutropenia: risks, consequences, and new directions for its management
Cancer
Severe neurotoxicity following 5-fluorouracil-based chemotherapy in a patient with dihydropyrimidine dehydrogenase deficiency
Clin Cancer Res
Nephrotoxicity from chemotherapy: prevention and management
Oncology
Frequency and cost of chemotherapy-related serious adverse effects in a population sample of women with breast cancer
J Natl Cancer Inst
Multilineage potential of adult human mesenchymal stem cells
Science
Pluripotency of mesenchymal stem cells derived from adult marrow
Nature
Phenotypical and functional properties of human bone marrow mesenchymal progenitor cells
J Cell Physiol
Mesenchymal and haematopoietic stem cells form a unique bone marrow niche
Nature
Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials
Haematologica
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These authors contribute equally to this work. Guo-Hu Di, Shu Jiang and Hai-Feng Duan designed, performed and analyzed the experiments, and wrote and revised the manuscript; Fu-Quan Li and Jun-Zhong Sun performed and analyzed the experiments; Chu-Tse Wu and Xiang Hu analyzed the experiments and revised the manuscript.