Mesenchymal stem cells as therapeutics

Abstract

Mesenchymal stem cells (MSCs) are multipotent cells that are being clinically explored as a new therapeutic for treating a variety of immune-mediated diseases. First heralded as a regenerative therapy for skeletal tissue repair, MSCs have recently been shown to modulate endogenous tissue and immune cells. Preclinical studies of the mechanism of action suggest that the therapeutic effects afforded by MSC transplantation are short-lived and related to dynamic, paracrine interactions between MSCs and host cells. Therefore, representations of MSCs as drug-loaded particles may allow for pharmacokinetic models to predict the therapeutic activity of MSC transplants as a function of drug delivery mode. By integrating principles of MSC biology, therapy, and engineering, the field is armed to usher in the next generation of stem cell therapeutics.

Figure 1

A brief history of mesenchymal stem cells (MSCs). Abbreviation: Tx, transplantation.

Figure 2

Natural functions of mesenchymal stem cells (MSCs) in the bone marrow. (a) MSCs can differentiate into skeletal tissue cells within the marrow cavity. (b) MSCs secrete a number of soluble factors that are involved in hematopoietic development. (c) Given their purported perivascular localization, MSCs may serve cellular functions similar to pericytes that surround bone marrow sinusoids. (d ) MSCs maintain the mechanical microenvironment of the marrow by secreting and remodeling ECM. Abbreviation: ECM, extracellular matrix.

Figure 3

Potential risks associated with MSC transplantation. (a) MSCs have been shown to maldifferentiate into glomerular adipocytes and osteosarcomas when administered systemically. (b) Systemic administration of MSCs may impair immune surveillance, making the recipient more susceptible to opportunistic infections. (c) When transplanted with cancer cells, MSCs can adapt a tumor-associated fibroblast phenotype and support the growth of the cancer by directly promoting tumor growth, metastasis, and angiogenesis. Abbreviations: MSC, mesenchymal stem cell; TAF, tumor-associated fibroblast.

Figure 4

Representative studies describing the in vivo distribution of MSCs upon systemic administration. Tracking studies generally consist of intravenous injection of the cells and then tracking of the cells using a variety of known methods. The representative studies featured here used two sensitive methods available for whole-organism analysis: polymerase chain reaction of a human gene to quantify human MSC engraftment in a number of mouse tissues, and MSCs labeled with luciferase to qualitatively trace their engraftment. Abbreviation: iv, intravenous.

Figure 5

Pharmacokinetic analysis of MSC therapy. (a) Schematic of two-compartment pharmacokinetic model of MSC drug delivery incorporating the following parameters: R_i, injection rate; R_c, clearance rate; K₁, rate of extravasation; K₂, rate of intravasation. (b) Theoretical engraftment of MSCs with a hypothetical retention of nearly 100% of MSCs over the course of 120 h. The apparent activity is the product of the unit activity per cell and the number of cells remaining after injection. Assuming a minimum effective activity level well below the apparent activity, the biological response would be expected to rise as soon as the minimum effective activity level is reached and to be sustained thereafter. (c) Apparent engraftment of MSCs with a decaying retention of MSCs. Assuming an exponential decay with a 24-h half-life, the apparent activity peaks above the minimum effective activity level only for a brief period of time. This results in a brief and temporary biological response that does not persist beyond 24 h. These data are consistent with the cytokine response associated with MSC transplantation or MSC-derived molecules when the latter were administered to animals undergoing systemic inflammation.