A Comparison of in vivo Tumor-Homing Abilities of Placental-Derived and Bone Marrow-Derived Mesenchymal Stromal Cells in High-Risk Neuroblastoma.

BACKGROUND: Neuroblastoma is a highly lethal malignancy of young children. Mesenchymal stromal cells (MSCs) may represent a novel cellular delivery vehicle due to their innate tumor-homing properties. We compared in vivo homing abilities of placental-derived MSCs (PMSCs) and bone marrow-derived MSCs (BM-MSCs) in an orthotopic neuroblastoma xenograft. METHODS: 28 mice underwent direct implantation of neuroblastoma cells (cell line NB1643) into the adrenal gland followed by intraperitoneal injection of 5 × 106 MSCs (PMSC n = 13, BM-MSC n = 13, PBS controls n = 2). MSC migration was monitored with in vivo imaging system (IVIS) radiance measurements at multiple timepoints post-MSC injection. Necropsy timepoints were 72 h (n = 10) and 7 days (n = 16). Ex vivo imaging was performed on all adrenal masses and select organ tissues. Immunohistochemistry (IHC) assessed the presence of MSCs in tumors. RESULTS: IVIS demonstrated initial diffuse signal that migrated to the left abdomen. Radiance decreased over time, but MSC signal persisted at day 7 in all animals. Ex vivo IVIS demonstrated signal in the adrenal tumor but not other organs. There was no significant difference in average ex vivo adrenal mass radiance between MSC groups (p = 0.74). IHC confirmed presence of both MSC types within the tumor. CONCLUSION: PMSCs and BM-MSCs successfully migrated to neuroblastoma tumor tissues in vivo without evidence of migration to other organs. MSCs migrate within 72 h and persisted within the tumor up to 7 days. There was no significant difference in homing capabilities of PMSCs compared to BM-MSCs, indicating that either cell type has potential as a drug delivery vehicle. TYPE OF STUDY: Original Research. LEVEL OF EVIDENCE: n/a.

Development of a Simple and Reproducible Cell-derived Orthotopic Xenograft Murine Model for Neuroblastoma.

BACKGROUND/AIM: Neuroblastoma is a common childhood cancer with poor survival for children with high-risk disease, and ongoing research to improve outcomes is needed. Patient-derived xenografts (PDX) and genetically engineered mouse models (GEMM) are reliable models for oncologic research; however, they are resource-intensive, expensive, and require significant expertise to develop and maintain. We developed an orthotopic xenograft murine model of neuroblastoma that utilizes cryopreserved banks of human neuroblastoma cell lines, requires minimal equipment, and is easily reproducible. MATERIALS AND METHODS: The neuroblastoma cell line NB1643 was obtained from the Children's Oncology Group (COG) Childhood Cancer Repository. Nod-SCID-gamma (NSG) mice underwent orthotopic injection of 2x106 NB1643 cells suspended in 10 µl of collagen hydrogel directly into the adrenal gland via an open retroperitoneal surgical approach. Mice were monitored by ultrasound and in vivo imaging system (IVIS) until the tumor reached the volume of the ipsilateral kidney. Tumor identity was confirmed by necropsy and histologic analysis. RESULTS: A total of 55 mice underwent surgery. Eight died due to anesthetic or surgical complications. 39/47 (78%) survivors grew primary adrenal tumors. Average anesthesia time was 30 min. Ultrasound and IVIS successfully characterized tumor growth in all mice. Average time to target tumor size was 5 weeks (range=3-9). Gross pathologic and histologic analysis confirmed adrenal tumors consistent with neuroblastoma in all mice with adrenal masses. CONCLUSION: A cell-derived orthotopic xenograft murine model can be successfully used to create an in vivo model of neuroblastoma. This model can be utilized in environments where PDX or GEMM models are not feasible.

Proliferative Effects of Mesenchymal Stromal Cells on Neuroblastoma Cell Lines: Are They Tumor Promoting or Tumor Inhibiting?

BACKGROUND: Neuroblastoma is a common pediatric malignancy with poor survival for high-risk disease. Mesenchymal stromal cells (MSCs) have innate tumor-homing properties, enabling them to serve as a cellular delivery vehicle, but MSCs have demonstrated variable effects on tumor growth. We compared how placental MSCs (PMSCs) and bone marrow-derived MSCs (BM-MSCs) affect proliferation of neuroblastoma (NB) cells in vitro. METHODS: Indirect co-culture assessed proliferative effects of 18 MSCs (early-gestation PMSCs (n = 9), term PMSCs (n = 5), BM-MSCs (n = 4) on three high-risk NB cell lines (NB1643, SH-SY5Y, and CHLA90). Controls were NB cells cultured in media alone. Proliferation was assessed using MTS assay and measured by fold change (fc) over controls. PMSCs were sub-grouped by neuroprotective effect: strong (n = 7), intermediate (n = 3), and weak (n = 4). The relationship between MSC type, PMSC neuroprotection, and PMSC gestational age on NB cell proliferation was assessed. RESULTS: NB cell proliferation varied between MSC groups. BM-MSCs demonstrated lower proliferative effects than PMSCs (fc 1.18 vs 1.44, p < 0.001). Neither gestational age nor neuroprotection significantly predicted degree of proliferation. Proliferative effects of MSCs varied among NB cell lines. BM-MSCs had less effect on CHLA90 (fc 1.01) compared to NB1643 (fc 1.33) and SH-SY5Y (fc 1.20). Only NB1643 showed a difference between early and term PMSCs (p = 0.04). CONCLUSION: Effects of MSCs on NB cell proliferation vary by MSC source and NB cell line. BM-MSCs demonstrated lower proliferative effects than most PMSCs. MSC neuroprotection was not correlated with proliferation. Improved understanding of MSC proliferation-promoting mechanisms may provide valuable insight into selection of cells best suited as drug delivery vehicles. LEVEL OF EVIDENCE: N/A. TYPE OF STUDY: Original Research.

What do spinal cord injury consumers want? A review of spinal cord injury consumer priorities and neuroprosthesis from the 2008 neural interfaces conference.

OBJECTIVE: To summarize research to understand the priorities of consumers with spinal cord injury (SCI) as related to neuroprosthesis. MATERIALS AND METHODS: This review is generated from results presented during a session at the 2008 Neural Interfaces Conference held in Cleveland, OH including presentations of research, observation of a panel discussion, and a case study. RESULTS: Understanding priorities of consumers living with SCI may help guide development of technology to potentially increase quality of life, confidence, and independence. Those living with quadriplegia desire arm and hand function while persons with paraplegia wish to regain sexual function. Shared priorities in the SCI population are the restoration of bladder and bowel function and the importance of exercise for functional recovery. CONCLUSION: Understanding the consumer is the cornerstone to successful delivery of a neuroprosthesis. Translational research by multidisciplinary teams is needed to understand these issues and move technology for people living with SCI from the bench to the bedside.