Pre-treatment of MSCs Can Reduce Their Regenerative Properties

Mesenchymal stem cells (MSCs) are excellent suppressors of unwanted inflammation.  This anti-inflammatory activity has been established for systemic inflammatory diseases in animal experiments (Klinker MW, Wei CH. World J Stem Cells. 2015 Apr 26;7(3):556-67), and in clinical trials with human patients (Dulamea A. J Med Life. 2015 Jan-Mar;8(1):24-7; Simonson OE et al., Stem Cells Transl Med. 2015 Oct;4(10):1199-213. doi: 10.5966/sctm.2015-0021).  Stem cell researchers have also shown that MSCs can suppress inflammation in the bowel (see Swenson E and Theise N. Clinical and Experimental Gastroenterology 2010;3:1-10; Chen Z, et al., Biochem Biophys Res Commun. 2014 Aug 8;450(4):1402-8).

After being introduced into the body of a patient, MSCs to move to the site where they are needed (a phenomenon known as “homing”) and promote tissue repair and healing.  Sometime MSC homing works quite well, but other times, it is so-so.  Therefore, several inventive scientists have devised ways to beef up homing to specific sites in order to improve MSC-based tissue healing.  Also, investigators are equally interested in increasing the ability of MSCs to stick to tissues once they arrive there to ensure that the homed MSCs stay where they are needed (see Kavanagh DP, Robinson J, and Kalia N. Stem Cell Rev 2014;10:587-599).  Unfortunately, at the moment, the whole homing process is a bit of a black box and while artificially increasing homing might help in the laboratory, whether or not it increases the therapeutic benefit of MSCs is even less well understood.

A new report from the laboratory of Neena Kalia, who works at the University of Birmingham, UK, has examined the effect of artificial enhancement on the therapeutic capacity of MSCs to treat inflammation in the bowel.  This is an important study because pre-treatment strategies have been suggested as ways to boost MSC homing and retention to various tissues.  The Kalia study suggests such pre-treatment strategies should be viewed with a degree of skepticism.

In this study, Kalia her coworkers induced inflammation in the gastrointestinal tracts of mice by clamping off the blood supply to the this tissue for a time and then releasing the clamps and letting the blood flow anew.  This type of damage, known as ischemia/reperfusion (IR) injury deprives cells of vital oxygen and nutrients for a short period of time, which causes some cells to die.  When the blood is allowed to flow into the tissue, inflammation is induced in the damaged tissue.  Therefore, this technique can efficiently induce  inflammation in tissues in the gastrointestinal tract.

Two groups of mice were treated with bone marrow-derived MSCs.  One group had experiences IR injury to their gastrointestinal tracts, and the other group did not.  In these experiments, administered MSCs showed similar levels of and cell adhesion in both injured and non-injured guts.  In general, cell adhesion levels were nothing to write home about:  as reported in the paper, “limited cell adhesion observed.”  Despite these initial observations, those MSCs that found their way to the gut were able to help heal the tissues to some degree.  There were fewer white blood cells in the middle part of the small intestine (jejunum), and the degree of blood flow seemed to have improved.  Unfortunately, the lower part of the small intestine (ileum) was not helped to the same degree, and the paper reports that a fair number of MSCs got stuck in small blood vessels, which suggests that these vessels got stuck on their way to the intestine.

If these results seem underwhelming, it might be because they are.  Undaunted, Kalia and her crew tried to boost the regenerative abilities of their isolated MSCs by pretreating them.  Kalia’s laboratory and other laboratories as well have used a variety of chemical agents to augment the healing abilities of MSCs.  These agents include things like tumor necrosis factor (TNF)-α, CXCL12 (also known as stromal cell-derived factor 1 or SDF1, which strongly activates white blood cells), interferon (IFN)-γ, or hydrogen peroxide.  When these pre-treated MSCs were administered to mice whose guts were damaged by means of IR injury, the pretreatment not only did not enhance their intestinal recruitment, but actually decreased the healing capacities of MSCs.  Pretreatment of MSCs with tumor necrosis factor (TNF)-α, CXCL12, interferon (IFN)-γ, or hydrogen peroxide did not enhance their intestinal recruitment.  Pretreatment with TNFα and IFNγ abrogated ability of transplanted MSCs to reduce white blood cells infiltration and improve blood flow in the jejunum.

Kalia and her colleagues utilized a technique called “intravital” microscopy for this study.  Intravital microscopy can track individual cells in a living animals (Kavanagh DP, Yemm AI, Zhao Y, et al. PLoS One 2013;8:e59150). With this technique, they were able to efficiently monitor adhesion in the tinyu blood vessels in the injured intestinal tissue.  They documented poor MSC adhesion to the gut lining and that pre-treatment with various factors hopes failed to enhance adhesion of MSCs to the gut.

This study successfully demonstrated that MSCs can rapidly limit white blood cells recruitment to the inflamed gut, and improve tissue perfusion if they are administered after intestinal IR injury. However, Kalia’s study also shows that strategies to improve MSC therapeutic efficacy by means of pretreatment of MSCs may not be all it’s cracked up to be.  They suggest that in the future, cytokine or chemical pretreatments designed to enhance MSC recruitment and function will require more than just successful experiments in a cell culture system.  Instead, pretreatment strategies will need to be carefully validated in living organisms in order the confirm that such protocols help rather than hinder the therapeutic function of implanted stem cells.

This paper was published in the journal Stem Cells – Kavanagh DP, Suresh S, Newsome PN, et al. Stem Cells 2015;33:2785-2797

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Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).

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