Drugs that Increase Bone Marrow Stem Cell Mobilization Improves Heart Healing After a Heart Attack in Laboratory Mice

The laboratory of Ahmed Abdel-Latif at the University of Kentucky has used an acute heart attack model in laboratory mice to examine if fatty signaling molecules have the ability to improve the healing of the heart after a heart attack.

A host of studies have examined the ability of transplanted stem cells to help heal the heart after a heart attack. Many laboratories have examined the efficacy of stem cells from bone marrow (Afzal MR, et al., Circ Res. 2015 Aug 28;117(6):558-75), fat (Suzuki E, et al., World J Cardiol. 2015 Aug 26;7(8):454-65), and umbilical cord blood (Xing Y, et al., Cell Mol Biol (Noisy-le-grand). 2014 Jun 15;60(2):6-12) to improve heart function, prevent remodeling, help heart muscle cells survive, and promote the growth of new blood vessels. Unfortunately, while these studies have produced largely positive results, such stem cell treatments lack consistency in their activity and efficacy.

Heart attacks result from oxygen deprivation of the heart. The lack of oxygen causes heart muscle cells to die off. Heart muscle cells are not like skeletal muscle cells, which can work at an oxygen deficit. Instead, the oxygen-deprived heart muscle cells will die even after a show period of ischemia. This cell death causes the release of a host of molecules into the vicinity of the heart muscle that induces a sizable inflammatory response, which kills off even more cells. This inflammatory response, however, has a positive side too, since it can send signals to the rest of the body, in particular the bone marrow, and mobilize stem cells into the blood steam that eventually home to the damaged heart tissue. Once in the heart, these cells can mediate repair of the damaged heart (see Hsieh PC, et al., Nature Medicine 2007;13:970-974; Abdel-Latif A, et al., Exp Hematol 2010;38:1131-1142; Finan A and Richard S, Frontiers in Cell and Developmental Biology 2015; 3: 57).

The nature of the signals that bring bone marrow stem cells to the doorstep of the damaged heart have been the subject of some interest to several laboratories. Work from several different laboratories have shown that bone marrow stem cells are held in the bone marrow by means of a molecule called stromal-derived growth factor-1 (SDF-1), which is made by the bone marrow cells that surround the stem cell that binds to a receptor on the surface of the bone marrow stem cell called-CXCR4. This SDF-1/CXCR4 interaction keeps the bone marrow stem cell happy with its location. And additional binding between a stem cell surface protein called Very Late Antigen-4 (VLA-4; α4β1 integrin) and a receptor for VLA-4 called Vascular Adhesion Molecule-1 (VCAM-1; CD106), which is found on the surfaces bone marrow cells, tethers the bone marrow stem cells to the bone marrow and bone marrow niches (see Lapidot T, Dar A, Kollet O. Blood. 2005;106(6):1901–1910; Peled A, et al., J Clin Invest. 1999;104(9):1199–1211;Lévesque JP, et al., Blood. 2001;98(5):1289–1297; Lévesque JP, et al., J Clin Invest. 2003;111(2):187–196).

Bone marrow stem cells can be mobilized into the peripheral blood by infection, tissue injury, or after the administration of particular pharmacological agents such as granulocyte colony stimulating factor (G-CSF) or some polysaccharides such as Zymosan. Earlier thinking focused on the protein SDF-1, because several papers seemed to suggest a role for SDF-1 in stem cell recruitment of tissue repair after injury (Bobadilla M, et al., Stem Cells Dev. 2014 Jun 15;23(12):1417-27; Wen J, Am J Cardiovasc Dis. 2012;2(1):20-8; Yang JX, et al., J Biol Chem. 2015 Jan 23;290(4):1994-2006). However, SDF-1 does not seem to be the major signaling molecule that mobilizes bone marrow stem cells after a heart attack, because stem cell mobilization is not blocked if an antagonist for CXCR4 called AMD3100 is administered (See Ratajczak and others below). Instead, a group of lipids that are precursors for the synthesis of a group of membrane lipids known as “sphingolipids” seem to be the main signaling molecules for this event (see Ratajczak MZ, et al., Leukemia 2010;24:976-985).


In particular, two molecules, sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) are probably the main players for this response. Thus, several stem cell scientists have predicted that giving people drugs that increase the concentrations of S1P and C1P might enhance healing of the heart after a heart attack through improved stem cell mobilization.

This is the point at which Ahmed Abdel-Latif and his colleagues com into the story, because Abdel-Latif’s lab used a drug called tetrahydroxybutylimidazole (THI) to do exactly that. THI inhibits an enzyme called S1P lyase (SPL), which degrades S1P. Therefore, THI raises the concentrations of S1p in the peripheral blood. Abdel-Latif and his coworkers administered THI to mice 4 days after they had suffered a heart attack. This time lag is essential because the first few days after the heart attack, the heart is a very hostile place, and any recruited or injected cells will die. However, 4 days is also well before scarring and scar formation occur in the heart.

Abdel-Latif and others observed that THI treatment lengthens the time period during which stem cells from the bone marrow are recruited and sent to the blood stream. The greater number of stem cells sent to the heart resulted in enhanced heart regeneration. The hearts of the THI-treated animals showed significantly better ejection fractions (average percentage of blood ejected from the ventricles per heart beat), increased heart wall thickness, and reductions in the size of the heart scar 5 weeks after their heart attacks.

When the mobilized bone marrow stem cells were isolated from peripheral blood and screened for gene expression, it was clear that these cells expressed a gaggle of stem cell homing, mobilization, cell survival, and blood vessel making genes. Thus, these mobilized stem cells were not only ready to go to the heart, but they were fully primed for to stimulate tissue healing.

Labeling studies also showed that bone marrow stem cells and progenitor cells flocked to the damaged hearts. The THI-treated mice had more than twice the number of labeled cells in their hearts at the edge of the infarct zone than the control animals 5 weeks after their heart attack. The THI-treated animals also showed significant increases in capillary densities in the THI-treated animals. As expected, there was no evidence that the mobilized bone marrow stem cells that differentiated into heart muscle cells. Thus, whatever benefits these cells convey to the heart is probably mostly by means of secreted exosomes, growth factors, and other mechanisms or so-called paracrine mechanisms.

This procedure worked rather well in laboratory mice. Can it work in human patients? That’s the $64,000 question. We have hints that increase bone marrow stem cells mobilization after a heart attack might improve recovery. However, this hint comes from a small clinical study in which levels of mobilized stem cells in the bloodstream after a cardiac event was correlated with clinical outcomes one year after the episode (Wyderka R, et al. Mediators Inflamm 2012;2012:564027). Such a study is at odds with studies that have pharmacologically mobilized stem cells from the bone marrow with intravenous G-CSF in patients after a heart attack with little benefit (Hilbert B, et al., CMAJ. 2014 Aug 5;186(11):E427-34; Archilli F., et al., Heart. 2014 Apr;100(7):574-81; Moazzami K, et al., Cochrane Database Syst Rev. 2013 May 31;5:CD008844. doi: 10.1002/14651858.CD008844.pub2). However, as noted in this paper, a drug called LX2931 is a THI analog and is already given as a treatment for rheumatoid arthritis, LX2931 is a safe drug and also inhibits SPL. Possibly future clinical trials that use either LX2931 or something akin to it will be tested in heart attack patients.