Human umbilical cord blood, a rich source of hematopoietic and mesenchymal stem cells, provides an interesting therapeutic source of primitive cells. Specifically, human umbilical cord blood stem cells (hUCBSC) involve neither ethical issues related to embryonic stem cells nor common serious side-effects such as graft-versus-host disease, which may occur with bone marrow stem cells. In addition, hUCBSC exhibit higher proliferation and expansion potential than their adult bone marrow counterparts [1]. Studies have demonstrated that hUCBSC influence their surrounding microenvironment in several ways: inhibiting neuronal death and apoptosis, controlling tumor proliferation and invasion, and inducing cell differentiation, neoangiogenesis, tissue repair and neuronal regeneration.

Earlier, we demonstrated that cell-to-cell contact plays an important role in the induction of apoptosis in glioma cells by hUCBSC [2]. However, more attention has recently been directed to the intercellular exchange of signaling molecules between stem cells and other surrounding cells. Studying the effect of hUCBSC on co-culturing with glioma cells, we collected microscopic evidence that strongly suggests an active outflow secretion from stem cells to surrounding media. Recently, we reported the effect of stem cells on matrix metalloproteinases, an important family of proteolytic enzymes involved in angiogenesis, inflammation and wound healing. In a spinal cord injury rat model, we demonstrated that hUCBSC treatment following spinal cord injury upregulates metalloproteinase-2 (MMP-2), reducing the formation of glial scar and thereby creating an environment suitable for endogenous repair mechanisms [3].

In addition to their important participation in angiogenesis, we demonstrated that MMPs contribute to cell migration. Utilizing a medulloblastoma tumor model, we observed that MMP-2 also mediates the tropism of hUCBSC to tumoral cells, and that MMP-2 inhibition is capable of repressing such stem cell tropism in an in vivo model [4]. Such interaction between hUCBSC and the surrounding environment may have profound effects on co-cultured glioma cells by attenuating uncontrolled cell cycle progression [5], inducing apoptosis, and reducing tumor migration [6].

The influence of the microenvironment upon stem cells has garnered special attention in recent years. Numerous studies argue that a class of molecules called chemokines (a subclass of chemotactic cytokines) are responsible for signaling and coordinating an important phenomenon called stem-cell ‘homing’ [7], in which stem cells are directed to tissues under critical conditions such as hypoxia [8], inflammation [9], irradiation [10] and tumoral growth [11]. Published literature suggests that these particular critical conditions dictate specific stem cell activity. For example, we observed that when coculturing with glioma cells, hUCBSC inhibit angiogenesis [12] while other scientists have demonstrated that stem cell transplantation after stroke induces angiogenesis [13]. Interestingly, recent studies have demonstrated that stem cells secretion may not be restricted to common intercellular paracrine factors, but might also involve other signaling molecules such as microvesicles containing microRNAs [14].

In summary, although cell-to-cell contact is one of the means by which stem cells regulate their surrounding environment, increasing evidence suggests that active secretion of signaling molecules from stem cells plays an important role in such interaction. Furthermore, recent evidence suggests that secretion involves not only the traditional cellular interaction including proteins and growth factors, but also intracellular signaling molecules such as microRNAs. The identification of such molecules as well as the proper understanding of the mechanism by which this interaction induces complex cellular processes, such as differentiation and apoptosis, poses a remarkable challenge to future molecular biologists.

This manuscript was prepared at the invitation of the Managing Editor of Brain Disorders & Therapy.