Mesenchymal stem cells as therapeutics and vehicles for gene and drug delivery

doi:10.1016/j.addr.2010.08.010

Advanced Drug Delivery Reviews

Volume 62, Issue 12, 30 September 2010, Pages 1156-1166

https://doi.org/10.1016/j.addr.2010.08.010 Get rights and content

Abstract

Mesenchymal stem cells (MSCs) possess a set of several fairly unique properties which make them ideally suited both for cellular therapies/regenerative medicine, and as vehicles for gene and drug delivery. These include: 1) relative ease of isolation; 2) the ability to differentiate into a wide variety of seemingly functional cell types of both mesenchymal and non-mesenchymal origin; 3) the ability to be extensively expanded in culture without a loss of differentiative capacity; 4) they are not only hypoimmunogenic, but they produce immunosuppression upon transplantation; 5) their pronounced anti-inflammatory properties; and 6) their ability to home to damaged tissues, tumors, and metastases following in vivo administration. In this review, we summarize the latest research in the use of mesenchymal stem cells in regenerative medicine, as immunomodulatory/anti-inflammatory agents, and as vehicles for transferring both therapeutic genes in genetic disease and genes designed to destroy malignant cells.

Section snippets

Isolation and characterization of MSC

In pioneering studies [1], [2] performed over 30 years ago, Friedenstein demonstrated that fibroblastoid cells obtained from the bone marrow were capable of transferring the hematopoietic microenvironment to ectopic sites, thus establishing the concept that the marrow microenvironment resided within the so-called stromal cells of the marrow. Years later, scientists began to explore the full potential of these microenvironmental cells, and results of these studies led to the realization that this

Sources of MSC

Although much of the work to date has focused on MSC isolated from adult bone marrow, it is important to realize that cells that appear phenotypically and functionally to be MSC have now been isolated by our group and others from numerous tissues, including brain, liver, lung, fetal blood, umbilical cord blood, kidney, and even liposuction material [19], [20], [21], [22], [23], [24], [25], [26]. The broad distribution of MSC throughout the body leads one to postulate that MSC are likely to play

MSC in regenerative medicine

The in vitro and in vivo differentiation of MSC into the various mesenchymal cell types found within the bone marrow, i.e. bone, cartilage, and fat, has now been described by numerous laboratories, and the conditions to bring about each of these differentiative pathways have been delineated in detail [7]. Recent studies employing microarrays [30], [41], [42], [43] have now begun to shed light on the molecular mechanisms responsible for commitment to and progression along each of these lineages,

MSC as trophic “factories”

One issue which has complicated interpretation of the data generated from the aforementioned studies in liver as well as those conducted looking at the potential of MSC to mediate repair in the heart and other organ systems, is the fact that a therapeutic benefit is often observed in the absence of any evidence of sustained engraftment of the transplanted MSC within the damaged organ. Instead, it appears that the transplantation of MSC somehow stimulates the damaged host organ to repair itself

MSC as vehicles for delivering therapeutic genes

While MSC possess tremendous therapeutic potential by virtue of their ability to lodge/engraft within multiple tissues in the body and both give rise to tissue-specific cells and release trophic factors that trigger the tissue's own endogenous repair pathways, gene therapists have realized that these properties are just the beginning of the therapeutic applications for MSC [24], [174], [175]. By using gene therapy to engineer MSC to either augment their own natural production of specific

Use of MSC as immunomodulatory/anti-inflammatory agents

In addition to their broad differentiative capabilities and their potential utility as gene delivery vehicles, MSC represent a rather unique cell from an immunological standpoint, since MSC are known to be relatively hypoimmunogenic. They do not normally express MHC class II or the co-stimulatory molecules CD80 and CD82, unless they are stimulated with IFN-γ. As such, they do not seem to serve as very good targets for lysis by cytotoxic T cells or NK cells, and do not really stimulate the

MSC as anti-cancer agents

Cancer represents another condition in which there is a selective need for new cells created by the forming tumor. Studies over the last several years have now revealed that MSC have the ability to “sense” this need, migrate to the forming tumor following intravenous administration, and contribute to the newly forming tumor “stroma”. While this may not seem ideal, since the MSC could, in fact, provide support to the growing tumor, this property has now been realized to present a very powerful

Conclusions

With numerous investigators around the globe having established and verified that MSC harbor the ability to cross embryonic germ layers and give rise to a wide range of what developmental biology had taught were tissue-specific cells, it is now clear that the differentiative capacity of MSC is far broader than anyone would have foreseen at the time Friedenstein originally described his bone marrow-derived CFU-F. In addition to this tremendous differentiative potential, the relative ease with

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