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. 2026 Mar 21;231(3):39. doi: 10.1007/s00429-025-03044-x

CD44 antagonism after traumatic brain injury influences the adult neurogenic niche and behavioral outcomes

Jaclyn Iannucci 1, Marita John 1, Stephen Oderinde 1, Gabriel Maisonnave Arisi 1, Victoria Arismendi 1, Aleksandr Pereverzev 1, Lee A Shapiro 1,✉
PMCID: PMC13005821  PMID: 41863645

Abstract

Traumatic brain injury (TBI) alters the neurogenic niche in the adult hippocampal dentate gyrus (DG), including alterations to astrocytes and the aberrant growth and migration of newborn granule cells (GCs). The astrocytes at the base of the DG granule cell layer (GCL) are one progenitor cell type that generates the newborn GCs and provides a scaffold for the newborn GCs to migrate into the hippocampal circuitry. These radial glial-like cells are also activated after TBI, resulting in the formation of an ectopic glial scaffold. One mechanism of astrocyte activation is through the activity of macrophage migration inhibitory factory (MIF) binding to its receptor CD74. Previous studies have shown that the astroglial response to TBI was reduced by ISO1, a MIF antagonist. A requisite for MIF/CD74 signaling is the presence of CD44 at the cell-surface CD74 receptor complex. However, the role of CD44 in the astrocytic response to TBI has not been investigated. Mice received a lateral fluid percussion injury (FPI) or sham injury, followed by treatment with verbascocide (VB), a CD44 antagonist, or vehicle. The results showed that VB treatment improved digigait motor performance and FPI-induced cognitive deficits in the pattern recognition test (PRT). VB treatment also prevented the hypertrophy of the radial glial-like astrocytes and mitigated the formation of the ectopic glial scaffold. Concomitant with rescuing the astrocyte hypertrophy, VB also inhibited the aberrant growth and migration of immature neurons in the hippocampal DG. Thus, CD44 can modulate the astrocytic response to FPI and can improve related brain structure and functional outcomes.

Keywords: Invariant chain, MHCII, CD74, Neurogenesis, Pattern separation, Fluid percussion injury, Radial glia

Introduction

Adult hippocampal neurogenesis has been widely described in the dentate gyrus (DG) of rodents, humans, and numerous other species (Aizawa et al. 2009; Altman 1962, 1963; Eriksson et al. 1998; Gage 2025; Guéneau et al. 1982; Kempermann et al. 2015; Knoth et al. 2010; Roy et al. 2000; Spalding et al. 2013; Toda et al. 2019). This adult neurogenic niche has been associated with cognitive and affective function. A number of physiological stimuli have been shown to alter the rate, migration, and differentiation of adult born hippocampal granule cells (GCs). These include exercise and environmental enrichment, which exert an enhancing and beneficial influence on the birth, survival, and functional integration of adult born GCs (Kempermann et al. 1997, 1998, 2002; van Praag et al. 1999a, b, 2005). Conversely, insults like traumatic brain injury (TBI) and epilepsy cause aberrant growth and integration of newborn GCs, leading to detrimental outcomes (Chirumamilla et al. 2002; Ibrahim et al. 2016; Jessberger et al. 2005; Lybrand et al. 2021; Parent et al. 2006; Shapiro 2017; Shapiro et al. 2011; Villasana et al. 2015).

The neuronal precursor cells in the adult hippocampus have been intensively studied and include the radial glial-like astrocytes in the subgranular zone (SGZ), located at the border of the granule cell layer (GCL) and hilus (Berg et al. 2018). These radial glial astrocytes can give birth to several types of daughter cells in the adult hippocampal neurogenic niche, including immature dentate GCs, transit amplifying cells, which are largely committed neuronal precursors, and astroglia (Kriegstein and Alvarez-Buylla 2009). After giving birth to immature GCs, the radial glial astrocytes cradle the newborn neurons and remain closely apposed as the newborn neurons sprout rudimentary processes and migrate towards the GCL (Ribak and Shapiro 2007; Seki and Arai 1999; Shapiro et al., 2005b). The radial glial-like mother cells also extend their radial process into the GCL, providing a scaffold for the migration of the newborn neuron into the GCL (Ribak and Shapiro 2007; Shapiro et al. 2005a, b). This mode of migration is reminiscent of locomotor migration described for newborn neurons during cortical development (Rakic 1972; Rakic and Nowakowski 1981).

Following TBI, alterations to the radial glial-like astrocytes have been reported in association with altered neurogenesis (Downing et al. 2025; Littlejohn et al. 2020; Mukherjee et al. 2020; Robinson et al. 2016; Shapiro 2017). These neurogenic changes include altered numbers of immature GCs, accelerated and ectopic migration, as well as aberrant process outgrowth and integration (Bielefeld et al. 2024; Carlson et al. 2014; Dash et al. 2001; Rice et al. 2003; Sun et al. 2005; Urrea et al. 2007; Villasana et al. 2015). Additionally, changes to the survival rates of newborn neurons after TBI have been reported (Clark et al. 2020). Importantly, the radial glial-like astrocytes can influence many of these neurogenic changes, including the formation of an ectopic glial scaffold that provides a substrate for aberrant neurogenesis after TBI (Robinson et al. 2016). However, few studies have targeted the astrocytes to improve the neurogenic niche after TBI.

CD44 is a cell surface molecule that can bind various ligands, including hyaluronan, cytokines, and matrix metalloproteinases (Dzwonek and Wilczynski 2015). Importantly, CD44 expression in the human brain has been found in the white matter and in glial cells, particularly astrocytes (Al-Dalahmah et al. 2024; Bignami and Dahl 1986; Bradford et al. 2024; Cruz et al. 1986; Girgrah et al. 1991; McKenzie et al. 1982; Moretto et al. 1993; Vogel et al. 1992). Developmentally, CD44 has been used to identify astrocyte-restricted precursor cells (Liu et al. 2004), and postnatally has also been identified in neuronal precursor cells (Naruse et al. 2013). CD44 deletion has also been shown to increase neuronal stem cell proliferation in the adult SGZ (Su et al. 2017). Intriguingly, human temporal lobe epilepsy resection hippocampal specimens revealed CD44 expression specific to fibrous-like astrocytes with long processes, including radial glial-like astrocytes extending processes through the GCL (Sosunov et al. 2014).

CD44 may also influence astrocytes via its role as a co-stimulatory factor as part of the macrophage migration inhibitory factor (MIF)/invariant chain (CD74) axis (Gore et al. 2008; Leng et al. 2003; Shi et al. 2006). Activation of MIF/CD74 signaling in the presence of CD44 results in downstream activation of NF-kB innate immune signaling, including astrocyte activation (Matza et al. 2001; Starlets et al. 2006). Antagonism of MIF-binding to CD74 inhibited the activated astrocytic response to a fluid percussion injury (FPI) model of TBI (Newell-Rogers et al. 2020). This is consistent with several studies showing that MIF antagonism inhibits astrocyte activation in various models of neurodegeneration (Li et al. 2015; Piri et al. 2021; Su et al. 2016; Xuan et al. 2023). However, the role of CD44 in mediating the radial glial-like astrocytes in the adult hippocampal neurogenic niche has not been previously explored following TBI.

Considering that FPI results in altered neurogenesis and the formation of an ectopic glial scaffold that involves the radial glial-like astrocyte precursor cells in the hippocampus (Robinson et al. 2016), it is possible that targeting CD44 may rescue the altered astrocyte and neurogenic response after FPI. Verbascocide (VB) suppresses CD44 by antagonizing its dimerization (Wang et al. 2020a, b). VB has been shown to be neuroprotective (Burgos et al. 2020; Liang et al. 2016; Wang et al. 2020a, b) and anti-inflammatory (Alipieva et al. 2014), including reducing astrocyte activation in a mouse model of Alzheimer’s disease (Chen et al. 2022). Therefore, this study was designed to determine the astrocytic, neurogenic, and behavioral effects of antagonizing CD44 with VB treatment after a FPI in mice.

Methods

Animals

Male C57bl/6J (Jackson Laboratory, Bar Harbor, ME; Stock #000664) were purchased from Jackson Laboratories and allowed to acclimate for 1 week prior to experimental start. All mice were housed individually in ventilated cages in a controlled environment and maintained on a standard diet for the duration of the experiment. All work was approved by the Texas A&M Institute for Animal Care and Use Committee (IACUC) (AUP#2020 − 0140). At 12 weeks of age mice received either sham or FPI, followed by drug administration. Treatment groups were Sham + Vehicle (Veh), Sham + Verbascocide (VB), FPI + Veh, and FPI + VB. Following surgery and drug administration, tissue was collected at 3 days post-injury (DPI), or mice were kept for behavior testing at 21 DPI, n = 8.

Fluid percussion injury

Lateral FPI was used as a model of TBI as previously described (Iannucci et al. 2024; Mukherjee et al. 2013; Newell-Rogers et al. 2020; Tobin et al. 2014). Briefly, mice were anesthetized with isoflurane, prepped, cleaned, and shaved. Mice were placed in a stereotaxic instrument (Stoelting, Co., Wood Dale, IL) and a 2-mm craniectomy was made over the left parietal cortex, at -1.5 mm antero-posterior and 1.2 mm medio-lateral from the bregma, making sure to keep the dura intact. The female end of a Luer-Lok syringe was secured over the craniectomy with dental cement. Mice were then connected to the fluid percussion instrument (Custom Design & Fabrication, Model 01-B; Richmond, VA) via the male Luer-Lok attachment. A 12–16 ms FPI was delivered at a pressure of ~ 1.2–1.5 atm. Sham mice received identical treatment except a pressure pulse was never delivered. After injury or sham, suture was used to close the scalp over the wound and mice were returned to their home cage resting on a heating pad. Mice were monitored to ensure they resumed normal walking, feeding, drinking, and grooming behavior.

Drug administration

At 30 min post sham or FPI, mice were treated with VB (Cayman Chemical Company Cat, Ann Arbor, MI; #24965) 100 mg/kg intraperitoneal (i.p.) to antagonize CD44. VB was dissolved in dimethyl sulfoxide (DMSO) and further diluted with sterile saline. Vehicle-treated animals received equal volume DMSO in sterile saline.

Digigait

Our FPI model consistently yields a transient contralateral hindlimb deficit that resolves within 5–7 days after injury. To confirm this deficit, the digigait system (Mouse Specifics Inc., Framingham, MA) was used to assess acute changes in gate after FPI or sham procedure as previously described (Iannucci et al. 2024). Mice were acclimated to the room and trained to walk on the digigait at 12 cm/s 3 days prior to surgery. One day after FPI or sham, mice walked on the digigait and videos were recorded for analysis. Analysis was done using the digigait software (Mouse Specifics Inc., Framingham, MA), and metrics of interest included Paw Placement Positioning, an index of stance symmetry.

Pattern recognition test (PRT)

At 21 DPI, the PRT was used to measure the ability of mice to recognize pattern separation, as previously described (Iannucci et al. 2022, 2024). The PRT was incorporated into this study to assess a hippocampal-dependent task that is linked to intact neurogenesis (Clelland et al. 2009). The test comprised of 3 successive trials separated by a 1-hour intertrial interval. Mice were previously acclimated to the open field box. In the first trial, mice were placed in the open field box with a first set of two identical objects (shape 1 objects) positioned on floor pattern 1 (P1) and allowed to freely explore both objects for 5 min. In the second trial, mice were placed in the open field box with a second set of identical objects (shape 2 objects) on floor pattern 2 (P2) and again allowed to freely explore both objects for 5 min. In the third and final trial, one of the shape 2 objects from trial 2 was replaced with a shape 1 object on P2. This shape became the novel object (NO), and the shape 2 object became the familiar object (FO) on the P2 floor. Again, the mice were allowed to freely explore both objects for 5 min. Each trial was video recorded and analyzed using automated EthoVisionXT video tracking software (Noldus, Leesburg, VA). Additional scoring was done manually by a rater blind to the condition of the mice, in which the visits to each object were counted. A discrimination index (DI) was calculated to determine preference for one object over the other. The DI was calculated as (number of visits to the novel-number of visits to the familiar)/total number of object visits.

Immunohistochemistry

Immunohistochemistry was used to assess GFAP + astrocytes and doublecortin (DCX) + immature neurons in the hippocampal DG, as previously described (Iannucci et al. 2022; Ribak and Shapiro 2007; Robinson et al. 2016; Shapiro et al., 2005b). Briefly, mice were anesthetized with Fatal Plus (Sodium Pentobarbital; 52 mg/kg, administered i.p.) and transcardially perfused with PBS through the left ventricle until the blood ran clear. This was followed by 4% paraformaldehyde (PFA) through the left ventricle. All brains were allowed to postfix in the skull for 24 h in PFA, after which they were extracted and fixed for an additional 24 h in 4% PFA. Fixed brains were cut into 44-µm thick serial sections with a freezing microtome (American Optical Corp; Model #860). For GFAP, slices were stained with mouse anti-GFAP-Cy3 conjugated antibody (Sigma-Aldrich, St. Louis, MO; #C9205; RRID: AB_476889; 1:500) overnight at room temperature. For DCX, slices first underwent antigen retrieval in citrate buffer at 45° C for one hour and were subsequently stained with primary goat anti-DCX antibody (Santa Cruz Biotechnology, Dallas, TX; #sc-8066; RRID: AB_2088494; 1:200) overnight at room temperature, followed by secondary biotinylated donkey anti-goat IgG-Alexafluor-555 (Invitrogen, Waltham, MA; #A21432; RRID: AB_2535853; 1:200) for 1.5 h. For co-staining, GFAP was stained using rabbit anti-GFAP primary antibody (Sigma-Aldrich, St. Louis, MO; #G9269; RRID: AB_477035; 1:500) overnight at room temperature, followed by goat anti-rabbit IgG-AlexaFluor-488 (Invitrogen, Waltham, MA; #A21432; RRID: AB_2534069; 1:200) for 1.5 h. All slices were mounted and cover-slipped with antifade reagent (Vector Laboratories, Newark, CA; H-1200-10).

Imaging for all immunohistochemistry was done on a fluorescent microscope (Olympus, Bethlehem, PA). Sections (~ every 260–350 μm apart) containing the dorsal hippocampus (Bregma − 1.34 through − 2.80) were selected for analysis. A minimum of 2 slices were counted per animal, per antibody, within the stereological coordinates indicated above. The area of GFAP + radial glial cells was assessed using ImageJ. Within ImageJ, the boundaries of the regions of interests (ROIs) were drawn around the subgranular zone. To eliminate labeled elements smaller than 5 microns, the threshold function was used to convert each image into a binary image, as previously described (Robinson et al. 2016). The average area of GFAP + cells and processes was first assessed using the ‘Assess Particles’ function on ImageJ, with the minimum cutoff of 5.01 microns. From these measurements, the average area per GFAP + cell was calculated by dividing the total number of cells and processes counted in the image, by the total area of GFAP + staining of those included cells and processes.

Nissl stain

Cresyl violet staining was performed as previously described (Mukherjee et al. 2013). Briefly, sections were mounted onto gelatin-coated slides and allowed to dry overnight. Slides were then dehydrated and defatted in 70, 95, and 100% ETOH, followed by rehydration and staining in the cresyl violet solution (Sigma-Aldrich, St Louis, MO). Slides were rinsed in de-ionized H2O, again dehydrated, cleared with xylene, and coverslips were applied using permount. Sections were then visualized using an Olympus VS120 Slide Scanner (Evident Scientific; Tokyo, Japan). Analysis of lesion volume was conducted in OlyVIA (Evident Scientific; Tokyo, Japan) using the Cavalieri method.

Statistical analysis

Statistical analysis was carried out using GraphPad Prism (GraphPad Software Inc., Boston, MA; Version 9.0). Prior to statistical analysis all data were analyzed for outliers using the ROUT algorithm in GraphPad Prism, Q = 1%, as previously described (Iannucci et al. 2022). One outlier was removed based on this algorithm. Digigait and immunohistochemical data were analyzed by one-way analysis of variance (ANOVA) with post-hoc testing using the Holm-Sidak correction. Lesion volume was analyzed using a two-tail Student’s t-test. For the PRT, a one-sample Wilcoxon T-Test was used to assess preference for the novel object. For all statistical testing, significance was considered p < 0.05.

Results

CD44 antagonism improves FPI-induced motor and cognitive impairment and is neuroprotective

Inhibiting CD74-associated signaling after FPI has previously been shown to improve FPI-related deficits in motor function (Iannucci et al. 2024) and to reduce peri-injury lesion size (Tobin et al. 2014). Consistent with previous studies demonstrating motor impairments, FPI induced a significant deficit in balance and symmetry in the right (contralateral to the injury) hind paw (p < 0.05 vs. Sham + Veh). This motor impairment was significantly reduced by VB treatment (p < 0.05; Fig. 1B). FPI also induced a deficit in the PRT, with FPI + Veh mice failing to exhibit a preference for the novel object. Treatment with VB after FPI restored the preference for the NO (p < 0.05; Fig. 1C). Assessment of the peri-injury area using Nissl-stained tissue showed that the lesion volume in the FPI + Veh mice was larger than the FPI + VB mice at 3 DPI, though this was not significant (p = 0.29, ns; Fig. 1D-E). These data suggest that VB treatment may be neuroprotective after FPI, and this neuroprotection is accompanied by improvements in motor and cognitive performance. Importantly, pattern separation ability has been linked with neurogenesis in numerous experimental models, including TBI (França et al. 2017; Iannucci et al. 2022, 2024). Thus, it is important to examine the neurogenic niche.

Fig. 1.

Fig. 1

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CD44 antagonism improves motor and cognitive impairment, and is neuroprotective. In A, a schematic diagram of the experimental design is shown. In B, digigait analysis revealed an FPI-induced motor deficit, as measured by a significant increase in paw placement positioning at 1 DPI. This deficit was significantly improved by VB treatment after FPI. In C, FPI significantly impaired performance in the pattern recognition test (PRT) at 21 DPI, indicated by no preference for the novel object (NO). No such deficit was observed in the VB-treated FPI mice. In D, FPI induced the typical ipsilateral cortical lesion, and quantitative analysis of Nissl-stained tissue showed no significant differences between FPI + Veh and FPI + VB lesion size. In E, representative Nissl-stained tissue from Sham + Veh, FPI + Veh, and FPI + VB at 3 DPI illustrates the lesions in these two mice. It is pertinent to note that although the results were not significant, there does appear to be a slight albeit non-significant reduction in lesion size in the VB-treated mice. Data are Mean ± SEM, n = 6–8 per group. Scale bar in E is 1 mm. Note: one mouse was removed from the lesion volume analysis for FPI + Veh following outlier analysis (D). *p < 0.05

The ectopic glial scaffold

The rodent hippocampal DG is unique in that neurogenesis persists for much of the lifespan. In this neurogenic niche, GFAP + radial glial-like cells are one of the neuronal precursor cells. These radial glial-like astrocytes give birth to the newborn neurons and provide a scaffold for the growth, migration, and integration of the newborn neurons into the granule cell layer (Ribak and Shapiro 2007; Shapiro et al. 2005a, 2005b). However, following TBI, the radial glial-like astrocytes at the base of the GCL undergo morphological transformation into an ectopic glial scaffold (Robinson et al. 2016; Shapiro et al. 2005a; Shapiro and Ribak 2005). The ectopic glial scaffold provides an anatomical substrate for the aberrant growth and integration of the newborn neurons (Ribak and Shapiro 2007; Shapiro et al. 2005a, b). In the current study, FPI reproduced the formation of the ectopic glial scaffold (Figs. 2 and 3). Assessment of astrocytes in the SGZ of the DG was performed to further define the changes to these astrocytes. The results showed that in the FPI + Veh mice the radial glial-like astrocytes at the hilar/GCL border were significantly hypertrophied, such that they were larger than those in Sham + Veh mice (p < 0.05; Fig. 2D). These hypertrophied astrocytes were preferentially oriented with their lead process towards the hilus (Fig. 3). Treatment with VB after FPI mitigated the enlargement and aberrant orientation of these astrocytes.

Fig. 2.

Fig. 2

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Fluid percussion injury induced astrocyte hypertrophy in the DG at 3 DPI. Representative micrographs of GFAP+ (red) radial glia in the DG of Sham + Veh A, FPI + Veh B, and FPI + VB (C). Note that in B, many of the GFAP + astrocytes in the DG appear thickened and enlarged, relative to the sham mice in A. These enlarged cells include the radial glia along the border of the granule cell layer and the hilus (white arrowheads) as well as in the hilus (yellow arrowheads) of the FPI + Veh mice. These changes were not observed in the FPI + VB mice. In D, quantification of the average size of GFAP + radial glial cells at the border between the hilus and GCL showed that the average area of the astrocytes were significantly increased in FPI + Veh mice compared to Sham + Veh. This effect was ameliorated by VB treatment after FPI such that no significant differences were observed. Therefore, VB appears to mitigate the astrocytic response to FPI. Data are Mean ± SEM, n = 6–8 per group. *p < 0.05. Scale bar in C = 50 μm for all figures A-C

Fig. 3.

Fig. 3

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Normal and aberrant growth of DCX + cells along the GFAP + radial glial cell processes in the DG at 3 DPI In A-C, confocal micrographs depict the normal appearance of DCX + immature neurons (red) and GFAP + astrocytes (green) at the hilar/granule cell layer (GCL) border. In A, note the typical appearance of DCX + apical dendrites (yellow arrowheads) coursing and branching through the GCL into the molecular layer (ML). In B, the GFAP + radial glial processes are shown traversing through GCL (white arrowheads). In C, the combined channels shows that the DCX + apical dendrites extend along the GFAP + radial glial scaffold. In D-F, confocal micrographs of DCX + cells (red) and GFAP + radial glia (green) illustrating aberrant growth after FPI. In D, a basal dendrite is shown (yellow arrowheads) extending into the hilus. In E, numerous hypertrophied astrocytes are shown, with process oriented towards the hilus (white arrowheads). Note the paucity of GFAP + radial glial process coursing through the GCL, consistent with previous studies (Robinson et al. 2016; Shapiro et al. 2005a). In F, the basal dendrites can be seen coursing into the hilus along the hypertrophied GFAP + astrocytic processes (purple arrowhead). Scale bars in A-C = 10 μm, D-F = 20 μm

Basal dendrites and hilar ectopic granule cells

Previous studies in the FPI mouse model of TBI have identified basal dendrites from adult born GCs sprouting into the hilus along the ectopic radial-glial scaffold (Robinson et al. 2016). Consistent with these findings, the FPI + Veh mice exhibited hilar basal dendrites that were closely apposed to the process of the GFAP + radial-glial like cells (Figs. 3D-F and 4A and B). Many of the basal dendrites were horizontally oriented along the hilar/GCL border, although some were curving into the GCL, as the so-called recurrent basal dendrites (Dashtipour et al. 2002; Ribak et al. 2004; Shapiro et al. 2005a; Yan et al. 2001). The FPI + Veh mice also exhibited numerous hilar ectopic granule cells (Fig. 4C, D), consistent with previous studies (Robinson et al. 2016; Shapiro 2017). The aberrant migration of the immature GCs was mitigated by VB treatment, such that the FPI + VB mice exhibited little to no ectopic DCX + granule cells in the hilus.

Fig. 4.

Fig. 4

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Hilar basal dendrites and hilar ectopic cells in the DG at 3 DPI In A, a DCX + hilar basal dendrite is shown extending from the cell body into the hilus (white arrowheads). In B, this hilar basal dendrite is closely apposed to a GFAP + process (yellow arrowhead). This apposition is enlarged in the inset shown in A to highlight this relationship. In C and D, an example of hilar ectopic granule cells after FPI (white arrowheads). In D, these DCX + cells are partially cradled by GFAP + cells and processes (yellow arrowheads). These hilar ectopic cells are enlarged in the inset in C to highlight 4 DCX + cells in this cluster of hilar ectopic granule cells. Scale bars in A, B = 10 μm for all images

Discussion

The MIF/CD74 axis has been identified as a potentially high-yield therapeutic target for neurological disorders, including TBI (Denkinger et al. 2003; Kithcart et al. 2010; Matejuk et al. 2024; Nasiri et al. 2020; Newell-Rogers et al. 2020). While studies have antagonized MIF to inhibit MIF/CD74 immune signaling, the current study used VB to target CD44, a co-stimulatory factor of the MIF/CD74 signaling axis. The results from the current study show that VB at 30 min after FPI mitigated motor and cognitive impairment and improved anatomical outcomes in the hippocampus. A limitation of the current study is that it did not distinguish between the effects of VB on CD44 signaling, compared to the effects of VB on MIF/CD74 signaling, both of which have been implicated in astrocyte activation. Despite this limitation, VB mitigated the TBI-induced ectopic glial scaffold and reduced the aberrant growth and migration of immature neurons in the DG. These findings expand on the pathogenic mechanisms of CD44 that have been shown in clinical and pre-clinical multiple sclerosis, temporal lobe epilepsy, and cancers (Al-Dalahmah et al. 2024; Girgrah et al. 1991; Sosunov et al. 2014; Wang et al. 2020a, b).

In addition to the improved motor performance, VB treatment after FPI improved cognitive function, as measured by improved pattern separation performance. This pattern separation test was selected for this study because it has been linked to adult hippocampal neurogenesis (França et al. 2017; Oomen et al. 2014; Yassa and Stark 2011). These findings are consistent with previous studies that have shown that ablation of adult hippocampal neurogenesis impaired pattern separation ability (Clelland et al. 2009), while interventions that enhance hippocampal neurogenesis, including exercise and genetic manipulations, improved pattern separation performance (Creer et al. 2010; Kodali et al. 2021; Sahay et al. 2011; Shetty et al. 2020). Moreover, a different study that antagonized Class II invariant peptide (CLIP), a cleavage product of CD74, improved the decreased neurogenesis in 5xFAD mice compared to age-matched WT, and concomitantly rescued pattern separation impairment (Iannucci et al. 2024). Thus, the MIF/CD74 axis seems to play important roles in aberrant changes to adult neurogenesis in response to TBI, and these changes are associated with performance in the PRT.

Hippocampal astrocytes are also a potential pathogenic mechanism following TBI, and they have been shown to be responsive to MIF antagonism with ISO1 after FPI (Newell-Rogers et al. 2020). Other studies have also reported pathological changes to the hippocampal astrocytes following TBI (Burda et al. 2016; Clark et al. 2019; Leonard et al. 2024; Newell-Rogers et al. 2020), including those at the base of the GCL, the so-called radial glial-like astrocytes (Robinson et al. 2016). Growing evidence supports an active role of these astrocytes in brain function, rather than being mere support cells, including the ability to amplify or suppress sensory input (Wang et al. 2023). Thus, in addition to their role in giving birth and providing guidance to their daughter neurons, the radial glial-like astrocytes at the base of the GCL may also be contributing to the cognitive components of the hippocampal circuitry. The pattern separation data from this and other studies support this possibility. Future studies are needed to more fully examine the intriguing possibility that astrocytes modulate newborn neuron function, and this is amenable to targeting through the MIF/CD74 axis.

In conclusion, the current study demonstrated that treating with VB after LFPI improved cognitive outcomes, concomitant with improving the adult hippocampal neurogenic niche. These findings build on the growing body of literature identifying the CD44 and/or the MIF/CD74 axis after TBI as a potential therapeutic target. As the MIF/CD74 axis has also been identified as a potential high-yield therapeutic target in other neurodegenerative disorders such as AD, follow-up studies are needed to more fully elucidate the effects of modulating CD44 on MIF/CD74-dependent and independent signaling on hippocampal astrocytic functioning.

Acknowledgements

This manuscript is published posthumously in memory of Mr. Stephen Oderinde, a dedicated young scientist and valuable and beloved member of our team. We are extremely grateful to Mr. Oderinde for performing the astrocyte image analysis for this manuscript.The authors would also like to acknowledge Ms. Reagan Dominy for her assistance with image acquisition, and Dr. Malea Murphy and the Integrated Microscopy & Imaging Laboratory (IMIL), at the Texas A&M College of Medicine. The schematic diagram was created using biorender.com.

Author contributions

JI performed histology, analyzed data, and wrote the manuscript; MJ designed experiments, performed FPI surgeries, and ran behavioral experiments; SO performed histology and microscopy and analyzed data; VA assisted with behavior, histology, and microscopic analysis; GMA assisted with histology and image analysis; AP analyzed data; LAS designed experiments, supervised the project, and wrote the manuscript.

Funding

This work was supported by National Institutes of Health (NIH) RO1NS104282 to LAS and by a NREF Medical Student Summer Research Fellowship (AANS/NREF) awarded to MJ (Fellow) and LAS (Mentor).

Data availability

The datasets generated during and/or analyzed during the current study are not publicly available due to ongoing studies and analysis but are available from the corresponding author on reasonable request.

Declarations

Conflict of interest

The authors declare no competing interests.

Ethical approval

All work was approved by the Texas A&M Institute for Animal Care and Use Committee (IACUC) (AUP#2020 − 0140).

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Jaclyn Iannucci and Marita John have contributed to this manuscript equally.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets generated during and/or analyzed during the current study are not publicly available due to ongoing studies and analysis but are available from the corresponding author on reasonable request.

Articles from Brain Structure & Function are provided here courtesy of Springer

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