Human umbilical cord mesenchymal stromal cells mitigate chemotherapy-associated tissue injury in a pre-clinical mouse model

Abstract

Background aims

Mesenchymal stromal cells (MSC) have been shown to be a promising candidate for tissue regeneration and cancer therapy. However, their therapeutic potential against chemotherapy-induced side-effects remains unclear.

Methods

We treated murine Lewis lung carcinoma (LLC) and xenograft human colon tumors with adriamycin (ADM) for 3 consecutive days followed by one intravenous (i.v.) injection of human umbilical cord (hUC) MSC for several cycles.

Results

MSC treatment mitigated ADM-induced cardiomyopathy, reduced the extent of ADM-induced apoptosis in intestinal crypts, suppressed body weight loss in mice treated with ADM and increased the survival rate of mice treated with a lethal dose of ADM. The examination of hematologic parameters indicated a moderate recovery in MSC-injected mice. Systemic administration of MSC did not increase the growth of murine LLC cells and human colon carcinoma in vivo while it strongly inhibited the lung metastases of LLC cells.

Conclusions

We evaluated the prophylactic and therapeutic action of hUC MSC on the chemotherapy agent ADM-induced side-effects in two different tumor models. Our observations suggest that MSC can be used as auxiliary means in chemotherapy for certain tumor types.

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.