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Combined Cell Therapy as an Enhanced Treatment for Traumatic Brain Injury

Review of “Combination therapy with Treg and MSC enhances potency and attenuation of inflammation after traumatic brain injury compared to monotherapy” from STEM CELLS by Stuart P. Atkinson

Research led by Scott D. Olson and Charles S. Cox, Jr. (University of Texas Health Science Center at Houston, Houston, Texas, USA) into cell therapies for traumatic brain injury has highlighted the ability of human mesenchymal stem cells (MSCs) and human cord blood‐derived regulatory T cells (Tregs) to inhibit microglia‐mediated inflammatory responses [1-3]. The dampening of secondary inflammatory within the brain may represent an effective means to ameliorate some of the long-term consequences of the primary mechanical injury [1, 4].

Given the existence of a range of studies suggesting the synergistic effects of a combined Treg and MSC therapy [5, 6], the team sought to explore the impact of this new, potentially exciting approach on the microglial response after traumatic brain injury. Reporting in STEM CELLS [7], Caplan et al. now highlight a significant decrease in systemic inflammation in response to the combination cell therapy and underscore the dosing schedule as an important parameter affecting therapeutic outcomes.

Initial in vitro evaluations using activated rat splenocytes primary cultures of rat microglia provided evidence that combined Treg and MSC therapy reduced the level of inflammatory cytokine production (e.g., interferon-gamma and tumor necrosis factor-alpha) compared to single-agent therapies, suggesting a heightened ability to modulate both systemic- and neuro-inflammatory responses. The authors note that the distinct cell therapies likely modulate the production of individual cytokines and chemokines to create a synergistic effect on inflammatory responses.

The in vivo evaluations of combined Treg and MSC therapy sought to explore the impact on microglial responses in male rats 14 days after traumatic brain injury using various dosing schedules. In agreement with the in vitro data, the combined Treg and MSC therapy provided the best therapeutic outcomes; however, the authors found evidence that the timing of infusions may have a significant effect on outcomes as the infusion of Tregs at 24 hours and MSC at 72 hours represented the only treatment strategy that decreased microgliosis in the injured hemisphere at 14 days after traumatic brain injury.

Future experiments by the authors will examine the effects of combined Treg and MSC therapy on long‐term outcomes, such as microglial analysis and behavioral testing to improve the translatability of these data, and explore differential responses in female rats given the likely significant sex-derived differences in the microglial response to traumatic brain injury [8].

For more on how combination cell therapies may improve outcomes in traumatic brain injury patients, stay tuned to the Stem Cells Portal!


  1. Cox Jr CS, Juranek J, and Bedi S, Clinical trials in traumatic brain injury: cellular therapy and outcome measures. Transfusion 2019;59:858-868.
  2. Caplan HW, Prabhakara KS, Kumar A, et al., Human cord blood-derived regulatory T-cell therapy modulates the central and peripheral immune response after traumatic brain injury. STEM CELLS Translational Medicine 2020;9:903-916.
  3. Jackson ML, Srivastava AK, and Cox CS, Jr., Preclinical progenitor cell therapy in traumatic brain injury: a meta-analysis. Journal of Surgical Research 2017;214:38-48.
  4. Kochanek PM, Dixon CE, Mondello S, et al., Multi-Center Pre-clinical Consortia to Enhance Translation of Therapies and Biomarkers for Traumatic Brain Injury: Operation Brain Trauma Therapy and Beyond. Frontiers in Neurology 2018;9:640.
  5. Negi N and Griffin MD, Effects of mesenchymal stromal cells on regulatory T cells: Current understanding and clinical relevance. STEM CELLS 2020;38:596-605.
  6. Takahashi T, Tibell A, Ljung K, et al., Multipotent Mesenchymal Stromal Cells Synergize With Costimulation Blockade in the Inhibition of Immune Responses and the Induction of Foxp3+ Regulatory T Cells. STEM CELLS Translational Medicine 2014;3:1484-1494.
  7. Caplan HW, Prabhakara KS, Toledano Furman NE, et al., Combination therapy with Treg and mesenchymal stromal cells enhances potency and attenuation of inflammation after traumatic brain injury compared to monotherapy. STEM CELLS 2021;39:358-370.
  8. Caplan HW, Cox CS, and Bedi SS, Do microglia play a role in sex differences in TBI? Journal of Neuroscience Research 2017;95:509-517.