Mesenchymal stem cell perspective: cell biology to clinical progress

Abstract

The terms MSC and MSCs have become the preferred acronym to describe a cell and a cell population of multipotential stem/progenitor cells commonly referred to as mesenchymal stem cells, multipotential stromal cells, mesenchymal stromal cells, and mesenchymal progenitor cells. The MSCs can differentiate to important lineages under defined conditions in vitro and in limited situations after implantation in vivo. MSCs were isolated and described about 30 years ago and now there are over 55,000 publications on MSCs readily available. Here, we have focused on human MSCs whenever possible. The MSCs have broad anti-inflammatory and immune-modulatory properties. At present, these provide the greatest focus of human MSCs in clinical testing; however, the properties of cultured MSCs in vitro suggest they can have broader applications. The medical utility of MSCs continues to be investigated in over 950 clinical trials. There has been much progress in understanding MSCs over the years, and there is a strong foundation for future scientific research and clinical applications, but also some important questions remain to be answered. Developing further methods to understand and unlock MSC potential through intracellular and intercellular signaling, biomedical engineering, delivery methods and patient selection should all provide substantial advancements in the coming years and greater clinical opportunities. The expansive and growing field of MSC research is teaching us basic human cell biology as well as how to use this type of cell for cellular therapy in a variety of clinical settings, and while much promise is evident, careful new work is still needed.

Keywords: Mesenchymal stem cells; Stem-cell research.

Fig. 1

Characteristics of MSCs. a MSCs can be readily isolated from bone marrow and adipose tissue but all tissues harbor MSC-like cells as part of the microvasculature. b The number of MSCs, indicated here as colony-forming units (CFU-F), isolated from bone marrow drops off after 15–20 yrs of age and continues to decrease. c MSCs are rare in bone marrow and are culture-expanded to achieve high numbers for research or therapeutic use. However, there is a decrease in the clonal complexity with increased passaging, but the effect of this process on MSC uses is unclear. d The MSCs are known to produce a large number of soluble or vesicle-bound growth factors and cytokines, as well as microRNAs, that can signal to other cells and tissues. e The culture-expanded MSCs can differentiate to multiple cell lineages under separate specific in vitro conditions. The standard chrondro-, osteo- and adipo- differentiation conditions are widely used but additional in vitro conditions promote smooth muscle and striated muscle gene expression; changing medium conditions can induce expression of cardiac and liver genes. Once differentiated, the MSCs express virtually all the hallmark genes of the differentiated cell types. Currently, the more prominent MSC therapeutic uses take advantage of the MSC’s production of factors and the responsiveness of other interacting cells, such as cells of the immune system (see Table 1).

Fig. 2

MSC interactions with cytoskeletal elements, cell−cell contacts, extracellular matrix and topography can have profound effects on multipotential MSCs. a Harvesting MSCs from a bone marrow niche with its condensed cell-rich environment and culturing them in vitro removes the cell−cell cadherin and connexin connections and replaces them with cell−substrate and cell−matrix interactions, as the cells produce more extracellular matrix. b The stiffness of the MSC culture surface and the nature of the environment have significant input to alter gene transcription and biological responsiveness of the MSCs through nuclear Lamin-A and YAP1 (b) and the surface curvature can transduce cytoskeletal influence over MSC potential. Also, dynamic stretching and 3D matrix materials can provide new approaches to understanding MSC responses and potential therapeutic applications.

Fig. 3

MSC—Immune cell interactions. Initial studies envisioned autologous use of MSCs. However, studies with immune cells demonstrated that MSCs are not immediately rejected by T cells and other immune cells, prompting the study of allogeneic MSCs in mutiple therapies. MSCs produce at least 11 factors known to affect immune cells. When interacting with T cells (pathways 1 and 5) MSCs cause a reduction in inflammatory T H1 and an increase in T Regs and T H2 cells with the concomitant decrease in IFNγ, increase in IL-10, IL-4 and IL-5. When MSCs interact with dendritic cells (pathways 2, 3,and 4) there is a decrease in proinflammatory mature DC1 with a decrease in TNF-α and IL-12, and an increase in immature DC and DC2, with increased expression of IL-10. When MSCs interact with natural killer cells (pathway 6) there is a decrease in the expression of IFNγ. When macrophages interact with MSCs (pathway 7), there is a decrease in the proinflammatory M1 phenotype and an increase in the anti-inflammatory M2 phenotype, with increased PGE2, TSG-6 and IL-1RA. MSCs can also reduce the secretion of antibodies from B cells (pathway 8) and inhibit bacterial growth by a direct or indirect mechanism (pathway 9). This figure is used with permission from Blood/Aggarwal and Pittenger and has been updated/modified from its original form.

Fig. 4

MSCs implanted in vivo in the infarcted left ventricle wall improve cardiac recovery in preclinical models and patient studies. A diagram of cellular therapy approaches tested with MSCs is shown. 1—Peripheral veinous infusion. 2—Endomyocardial delivery via injection catheter. 3—Direct myocardial injection during open chest surgery such as for coronary artery bypass grafting. 4—Delivery via intracoronary arteries. MSCs release anti-inflammatory factors and interact with endogenous cells to improve physiological outcome despite limited engraftment. Panels (a−d)—a Porcine female heart receiving male allo-MSC injection show greater repair processes with active stimulation of endogenous cardiomyocyte cell-cycle activity (phospho H3 staining) which are associated with greater functional recovery. b Following direct injection of male MSCs near the infarct border, there are increased phospho-H3 detected at 8 weeks in the infarct (IZ) and border zones (BZ) compared to the remote zones (RZ) away from the infarct. The error bars indicate the mean ± SEM. c, d Immunohistology of data in (a) and (b). Results of clinical delivery of MSCs (e) are shown with MRI cross-section of hearts from patients receiving standard of care or standard of care plus MSCs in the PROMETHEUS trial. The MSC-treated hearts showed smaller infarcts at 12 and 18 months. The MSC-treated patients also had greater heart function (ejection fraction) and stamina (6 min walk test). The error bars indicate the mean ± SEM. Figures reproduced with permission of Kluwers Wolter/Circulation Research/Hare.^,