Calpain inhibitor MDL28170 improves the transplantation-mediated therapeutic effect of bone marrow-derived mesenchymal stem cells following traumatic brain injury
Abstract Background Studies have shown that transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) protects against brain damage. However, the low survival number of transplanted BMSCs remains a pertinent challenge and can be attributed to the unfavorable microenvironment of the injur...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2019-03-01
|
| Series: | Stem Cell Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13287-019-1210-4 |
| _version_ | 1818305677427212288 |
|---|---|
| author | Jiangnan Hu Lefu Chen Xujun Huang Ke Wu Saidan Ding Weikan Wang Brian Wang Charity Smith Changhong Ren Haoqi Ni Qichuan ZhuGe Jianjing Yang |
| author_facet | Jiangnan Hu Lefu Chen Xujun Huang Ke Wu Saidan Ding Weikan Wang Brian Wang Charity Smith Changhong Ren Haoqi Ni Qichuan ZhuGe Jianjing Yang |
| author_sort | Jiangnan Hu |
| collection | DOAJ |
| description | Abstract Background Studies have shown that transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) protects against brain damage. However, the low survival number of transplanted BMSCs remains a pertinent challenge and can be attributed to the unfavorable microenvironment of the injured brain. It is well known that calpain activation plays a critical role in traumatic brain injury (TBI)-mediated inflammation and cell death; previous studies showed that inhibiting calpain activation is neuroprotective after TBI. Thus, we investigated whether preconditioning with the calpain inhibitor, MDL28170, could enhance the survival of BMSCs transplanted at 24 h post TBI to improve neurological function. Methods TBI rat model was induced by the weight-drop method, using the gravitational forces of a free falling weight to produce a focal brain injury. MDL28170 was injected intracranially at the lesion site at 30 min post TBI, and the secretion levels of neuroinflammatory factors were assessed 24 h later. BMSCs labeled with green fluorescent protein (GFP) were locally administrated into the lesion site of TBI rat brains at 24 h post TBI. Immunofluorescence and histopathology were performed to evaluate the BMSC survival and the TBI lesion volume. Modified neurological severity scores were chosen to evaluate the functional recovery. The potential mechanisms by which MDL28170 is involved in the regulation of inflammation signaling pathway and cell apoptosis were determined by western blot and immunofluorescence staining. Results Overall, we found that a single dose of MDL28170 at acute phase of TBI improved the microenvironment by inhibiting the inflammation, facilitated the survival of grafted GFP-BMSCs, and reduced the grafted cell apoptosis, leading to the reduction of lesion cavity. Furthermore, a significant neurological function improvement was observed when BMSCs were transplanted into a MDL28170-preconditioned TBI brains compared with the one without MDL28170-precondition group. Conclusions Taken together, our data suggest that MDL28170 improves BMSC transplantation microenvironment and enhances the neurological function restoration after TBI via increased survival rate of BMSCs. We suggest that the calpain inhibitor, MDL28170, could be pursued as a new combination therapeutic strategy to advance the effects of transplanted BMSCs in cell-based regenerative medicine. |
| first_indexed | 2024-12-13T06:30:22Z |
| format | Article |
| id | doaj.art-253c8fa6bb12447f88f09aac65dcbfbf |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-12-13T06:30:22Z |
| publishDate | 2019-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj.art-253c8fa6bb12447f88f09aac65dcbfbf2022-12-21T23:56:37ZengBMCStem Cell Research & Therapy1757-65122019-03-0110111310.1186/s13287-019-1210-4Calpain inhibitor MDL28170 improves the transplantation-mediated therapeutic effect of bone marrow-derived mesenchymal stem cells following traumatic brain injuryJiangnan Hu0Lefu Chen1Xujun Huang2Ke Wu3Saidan Ding4Weikan Wang5Brian Wang6Charity Smith7Changhong Ren8Haoqi Ni9Qichuan ZhuGe10Jianjing Yang11Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical UniversityZhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Intensive Care Unit (ICU), Hengdian Wenrong HospitalZhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical UniversityZhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Pharmaceutical Sciences, University of North Texas Health Science CenterDepartment of Pharmaceutical Sciences, University of North Texas Health Science CenterDepartment of Pharmaceutical Sciences, University of North Texas Health Science CenterBeijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical UniversityZhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical UniversityZhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical UniversityZhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical UniversityAbstract Background Studies have shown that transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) protects against brain damage. However, the low survival number of transplanted BMSCs remains a pertinent challenge and can be attributed to the unfavorable microenvironment of the injured brain. It is well known that calpain activation plays a critical role in traumatic brain injury (TBI)-mediated inflammation and cell death; previous studies showed that inhibiting calpain activation is neuroprotective after TBI. Thus, we investigated whether preconditioning with the calpain inhibitor, MDL28170, could enhance the survival of BMSCs transplanted at 24 h post TBI to improve neurological function. Methods TBI rat model was induced by the weight-drop method, using the gravitational forces of a free falling weight to produce a focal brain injury. MDL28170 was injected intracranially at the lesion site at 30 min post TBI, and the secretion levels of neuroinflammatory factors were assessed 24 h later. BMSCs labeled with green fluorescent protein (GFP) were locally administrated into the lesion site of TBI rat brains at 24 h post TBI. Immunofluorescence and histopathology were performed to evaluate the BMSC survival and the TBI lesion volume. Modified neurological severity scores were chosen to evaluate the functional recovery. The potential mechanisms by which MDL28170 is involved in the regulation of inflammation signaling pathway and cell apoptosis were determined by western blot and immunofluorescence staining. Results Overall, we found that a single dose of MDL28170 at acute phase of TBI improved the microenvironment by inhibiting the inflammation, facilitated the survival of grafted GFP-BMSCs, and reduced the grafted cell apoptosis, leading to the reduction of lesion cavity. Furthermore, a significant neurological function improvement was observed when BMSCs were transplanted into a MDL28170-preconditioned TBI brains compared with the one without MDL28170-precondition group. Conclusions Taken together, our data suggest that MDL28170 improves BMSC transplantation microenvironment and enhances the neurological function restoration after TBI via increased survival rate of BMSCs. We suggest that the calpain inhibitor, MDL28170, could be pursued as a new combination therapeutic strategy to advance the effects of transplanted BMSCs in cell-based regenerative medicine.http://link.springer.com/article/10.1186/s13287-019-1210-4Traumatic brain injuryBone marrow-derived mesenchymal stem cellsPreconditioningCalpain inhibitorMDL28170Transplantation |
| spellingShingle | Jiangnan Hu Lefu Chen Xujun Huang Ke Wu Saidan Ding Weikan Wang Brian Wang Charity Smith Changhong Ren Haoqi Ni Qichuan ZhuGe Jianjing Yang Calpain inhibitor MDL28170 improves the transplantation-mediated therapeutic effect of bone marrow-derived mesenchymal stem cells following traumatic brain injury Stem Cell Research & Therapy Traumatic brain injury Bone marrow-derived mesenchymal stem cells Preconditioning Calpain inhibitor MDL28170 Transplantation |
| title | Calpain inhibitor MDL28170 improves the transplantation-mediated therapeutic effect of bone marrow-derived mesenchymal stem cells following traumatic brain injury |
| title_full | Calpain inhibitor MDL28170 improves the transplantation-mediated therapeutic effect of bone marrow-derived mesenchymal stem cells following traumatic brain injury |
| title_fullStr | Calpain inhibitor MDL28170 improves the transplantation-mediated therapeutic effect of bone marrow-derived mesenchymal stem cells following traumatic brain injury |
| title_full_unstemmed | Calpain inhibitor MDL28170 improves the transplantation-mediated therapeutic effect of bone marrow-derived mesenchymal stem cells following traumatic brain injury |
| title_short | Calpain inhibitor MDL28170 improves the transplantation-mediated therapeutic effect of bone marrow-derived mesenchymal stem cells following traumatic brain injury |
| title_sort | calpain inhibitor mdl28170 improves the transplantation mediated therapeutic effect of bone marrow derived mesenchymal stem cells following traumatic brain injury |
| topic | Traumatic brain injury Bone marrow-derived mesenchymal stem cells Preconditioning Calpain inhibitor MDL28170 Transplantation |
| url | http://link.springer.com/article/10.1186/s13287-019-1210-4 |
| work_keys_str_mv | AT jiangnanhu calpaininhibitormdl28170improvesthetransplantationmediatedtherapeuticeffectofbonemarrowderivedmesenchymalstemcellsfollowingtraumaticbraininjury AT lefuchen calpaininhibitormdl28170improvesthetransplantationmediatedtherapeuticeffectofbonemarrowderivedmesenchymalstemcellsfollowingtraumaticbraininjury AT xujunhuang calpaininhibitormdl28170improvesthetransplantationmediatedtherapeuticeffectofbonemarrowderivedmesenchymalstemcellsfollowingtraumaticbraininjury AT kewu calpaininhibitormdl28170improvesthetransplantationmediatedtherapeuticeffectofbonemarrowderivedmesenchymalstemcellsfollowingtraumaticbraininjury AT saidanding calpaininhibitormdl28170improvesthetransplantationmediatedtherapeuticeffectofbonemarrowderivedmesenchymalstemcellsfollowingtraumaticbraininjury AT weikanwang calpaininhibitormdl28170improvesthetransplantationmediatedtherapeuticeffectofbonemarrowderivedmesenchymalstemcellsfollowingtraumaticbraininjury AT brianwang calpaininhibitormdl28170improvesthetransplantationmediatedtherapeuticeffectofbonemarrowderivedmesenchymalstemcellsfollowingtraumaticbraininjury AT charitysmith calpaininhibitormdl28170improvesthetransplantationmediatedtherapeuticeffectofbonemarrowderivedmesenchymalstemcellsfollowingtraumaticbraininjury AT changhongren calpaininhibitormdl28170improvesthetransplantationmediatedtherapeuticeffectofbonemarrowderivedmesenchymalstemcellsfollowingtraumaticbraininjury AT haoqini calpaininhibitormdl28170improvesthetransplantationmediatedtherapeuticeffectofbonemarrowderivedmesenchymalstemcellsfollowingtraumaticbraininjury AT qichuanzhuge calpaininhibitormdl28170improvesthetransplantationmediatedtherapeuticeffectofbonemarrowderivedmesenchymalstemcellsfollowingtraumaticbraininjury AT jianjingyang calpaininhibitormdl28170improvesthetransplantationmediatedtherapeuticeffectofbonemarrowderivedmesenchymalstemcellsfollowingtraumaticbraininjury |