Stem cells that quell inflammation shortly after traumatic brain injury (TBI) may also offer lasting cognitive gains, says the University of Texas Health Science Center.

In a recent article appearing in Stem Cells Translational Medicine, the team of Children’s Program in Regenerative Medicine Director Charles Cox reported they injected, into the blood of two groups of rats with traumatic brain injury (TBI), human multi-potent adult progenitor cells (MAPCs). They did this two, and 24, hours after the mice were injured. One group received two million cells per kilogram; the other, a dose five times stronger.

TBI can cause severe brain damage, and ongoing brain inflammation. Few drugs help. Half of patients with serious TBI need surgery. Mesenchymal stem cells like MAPCs have been shown to reduce short-term inflammation, and result in functional improvement, in mice with TBI. But few if any groups have gauged MAPCs’ long-term effects on TBI.

After four months in Cox’s study, rats getting the stronger dose continued experiencing less inflammation, and better cognition. Spatial learning was up; motor deficits were down.

The intravenous MAPCs did not cross the blood/brain barrier, Cox tells Bioscience Technology.  “We spent 18 months looking for them in the brain. There was little to no engraftment there.”

Instead, the cells “set up shop in the spleen, a giant reservoir of T and B cells. The MAPCs change the spleen’s output to anti-inflammatory cells and cytokines, which communicate with immune cells in the brain—microglia—and change their response to injury from hyper-to-anti- inflammatory. The cells alter the innate immune response to injury. We have shown this in a sequence of papers.”

Stefano Pluchino, a University of Cambridge neurologist who has worked with immune regulatory stem cells, says Cox’s study shows a “good dose response” on disability and behavior “after hyperacute, or acute, intravenous injection of MAPCs.” But he says description of the cells’ effects on microglia is “speculative. It is not clear whether these counts have been done on the injured brain hemisphere, and whether MAPC effects were observable on the unaffected hemisphere.”

Pluchino continues: “The distribution and half-life of these MAPCs (distributed by Athersys) is not clear” and has never been demonstrated convincingly in Athersys papers. “It is also not clear if effects in the Cox study were a ‘false positive,’ secondary to a paradoxical immune suppression the xenograft modulates.” That is, a false positive could occur because human cells in animal bodies rouse immune reactions. “It is not clear where in the body these MAPCs would work, either out or into the injured brain.” Nor are mechanism(s) of action clear, he says.

But, Pluchino adds: “Athersys is already in clinic with MAPCs in graft vs. host disease, myocardial infarction, stroke, progressing towards a phase I/II clinical trial in multiple sclerosis, and completing the pre-clinical work in traumatic brain and spinal cord injuries. Everything looks great. The company is solid. The data is convincing in terms of behavioral and pathological analyses. But the points I have raised are far from clarified.”

Cox agrees Pluchino's points have some validity. But, he says, human cells were used in rodents because the FDA wants studies to evaluate the exact cells headed for the clinic. “As we are not seeking engraftment of these cells, and would not plan to immunosuppress a trauma patient, we have not pursued animal models that use immunosuppression. Our study was designed with translationally relevant end-points, recognizing the limitations of not having a final mechanism of action determined. The growing consensus is there are many mechanism(s) of action in cell therapies.”

He agrees the paper’s description of the cells’ effects on microglia “is not truly a proof of mechanism.” But his group has developed a method to more accurately quantify microglia in mice. “We ultimately plan more mechanistic studies to define endogenous microglia versus infiltrating microglia and the effects of various cell therapies. “

Additionally, Cox says: “We have published work showing the majority of acutely infused MSCs and MAPCs are lodged in the lung after intravenous delivery. This was an acute study in non-injured animals, but others have shown similar data.” In a subsequent study, Cox’s group showed that the cells sequester in the spleen as have “groups in stroke models using umbilical cord cells. We think they work in the spleen.”

Finally, Cox notes it is unlikely the immune response prompted by the human MAPCs in the rodents constituted “a false positive.” The cells induced “a modulation of the innate immune response, and typically, the immune rejection of a transplant is associated with immune activation, not suppression. So it well may be a ‘true positive.’”