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Robust Neurogenesis in Chronic Stroke Monkeys Following Mesenchymal Stem Cell Transplantation Plus Intermittent Theta-burst Stimulation

ABSTRACT: A significant population of chronic stroke patients urgently requires more effective therapies due to functional plateaus and limited intervention options. Intermittent theta-burst stimulation (iTBS) has been increasingly adopted in chronic-phase ischemic stroke management. However, the efficacy decreases over time. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic strategy for chronic stroke management through multiple mechanisms. Whether combined MSC transplantation and iTBS confers superior synergistic efficacy warrants further investigation. In this study, human umbilical cord-derived MSCs were stereotactically injected into the penumbra of the brain parenchyma adjacent to infarct sites in cynomolgus monkeys with chronic-stage middle cerebral artery occlusion (MCAO)-induced ischemic stroke. iTBS commenced at 1 week post-transplantation (5 sessions/week until week 17). Behavioral tests, electrophysiological recordings, functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), and plasma proteomic analysis were conducted longitudinally, with terminal histological and spatial proteomic analysis at week 17. The results demonstrated that combined MSC/iTBS therapy enhanced motor function, reduced cortical excitation thresholds, shortened motor-evoked potential (MEP) latency, increased neural activity intensity/synchronization, strengthened functional connectivity, and optimized motor cortex metabolism. In addition to the commonly attributed therapeutic mechanisms of MSCs and iTBS, the combined therapy additionally triggered neurogenesis and stem cell chemotaxis, which was potentially mediated by iTBS-enhanced CXCL12 secretion from MSCs. Therefore, MSC/iTBS combination therapy can effectively treat chronic stroke through multiple mechanisms, particularly involving the activation of endogenous neural stem cells (NSCs), representing a promising interdisciplinary treatment strategy.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Macaca Mulatta (rhesus Macaque)

TISSUE(S): Brain, Blood Plasma, Stem Cell

SUBMITTER: Yuan-Huan Ma

LAB HEAD: Yue Lan

PROVIDER: PXD071582 | Pride | 2026-03-12

REPOSITORIES: Pride

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			Action	DRS
	Astral_20250325_ES906_DIA_8min_180SPD_CTR-1.raw	Raw
	Astral_20250325_ES906_DIA_8min_180SPD_CTR-2.raw	Raw
	Astral_20250325_ES906_DIA_8min_180SPD_CTR-3.raw	Raw
	Astral_20250325_ES906_DIA_8min_180SPD_Sti-1.raw	Raw
	Astral_20250325_ES906_DIA_8min_180SPD_Sti-2.raw	Raw

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Project description:We have previously reported that the deficiency of p53 alone or in combination with Rb (Rb-/- p53-/-) in adipose-derived MSCs (ASCs) promotes leiomyosarcoma-like tumors in vivo. Here, we hypothesized that the source of MSCs and/or the cell differentiation stage could determine the phenotype of sarcoma development. To investigate whether there is a link between the source of MSCs and sarcoma phenotype, we generated p53-/- and Rb-/-p53-/- MSCs from bone marrow (BM-MSCs). Both genotypes of BM-MSCs initiated leiomyosarcoma formation similar to p53-/- and Rb-/-p53-/- ASCs. In addition, gene expression profiling revealed a link between p53- or Rb-p53-deficient BM-MSCs and ASCs and muscle-associated sarcomagenesis. These data suggest that the tissue source of MSC does not seem a crucial factor in the development of a particular sarcoma phenotype. To analyze whether the differentiation stage defines the sarcoma phenotype, BM-MSCs and ASCs were induced to differentiate towards the osteogenic lineage, and both p53 and Rb were excised using Cre-expressing adenovectors at different stages along osteogenic differentiation. Regardless of the level of osteogenic commitment, the inactivation of Rb and p53 in BM-MSC-derived, but not in ASC-derived, osteogenic progenitors gave rise to osteosarcoma-like tumors which could be serially transplanted. This indicates that the osteogenic differentiation stage of BM-MSCs imposes the phenotype of in vivo sarcoma development, and that BM-MSC-derived osteogenic progenitors rather than undifferentiated BM-MSCs, undifferentiated ASCs or ASC-derived osteogenic progenitors, represent the cell of origin for osteosarcoma development. To analyse whether the BM-MSC and Fat-MSC (ASC) differentiation stage may define the sarcoma phenotype, RbloxP/loxPp53loxP/loxP BM-MSCs and ASCs were induced to differentiate towards the osteogenic lineage and both Rb and p53 were excised with adenoviral vectors expressing the Cre-recombinase gene (Ad-CMV-Cre) at different stages (day 0 and 10) along osteogenic differentiation. NSG mice were inoculated subcutaneously with 5M-CM-^W10^6 mutant cells. Animals were killed when tumors reached 1 cm3 or 150 days after infusion. Some of the obtained tumors were mechanically disaggregated to establish ex vivo MSC-transformed cell lines. Gene expression analysis was performed using: WT BM-MSCs and ASCs, Rb-/-p53-/- BM-MSCs and ASCs previously differentiated to the osteogenic lineage for 10 days and a tumor cell line derived from p53-/-Rb-/- BM-MSC differentiated to the osteogenic lineage for 10 days.

Project description:We have previously reported that the deficiency of p53 alone or in combination with Rb (Rb-/- p53-/-) in adipose-derived MSCs (ASCs) promotes leiomyosarcoma-like tumors in vivo. Here, we hypothesized that the source of MSCs and/or the cell differentiation stage could determine the phenotype of sarcoma development. To investigate whether there is a link between the source of MSCs and sarcoma phenotype, we generated p53-/- and Rb-/-p53-/- MSCs from bone marrow (BM-MSCs). Both genotypes of BM-MSCs initiated leiomyosarcoma formation similar to p53-/- and Rb-/-p53-/- ASCs. In addition, gene expression profiling revealed a link between p53- or Rb-p53-deficient BM-MSCs and ASCs and muscle-associated sarcomagenesis. These data suggest that the tissue source of MSC does not seem a crucial factor in the development of a particular sarcoma phenotype. To analyze whether the differentiation stage defines the sarcoma phenotype, BM-MSCs and ASCs were induced to differentiate towards the osteogenic lineage, and both p53 and Rb were excised using Cre-expressing adenovectors at different stages along osteogenic differentiation. Regardless of the level of osteogenic commitment, the inactivation of Rb and p53 in BM-MSC-derived, but not in ASC-derived, osteogenic progenitors gave rise to osteosarcoma-like tumors which could be serially transplanted. This indicates that the osteogenic differentiation stage of BM-MSCs imposes the phenotype of in vivo sarcoma development, and that BM-MSC-derived osteogenic progenitors rather than undifferentiated BM-MSCs, undifferentiated ASCs or ASC-derived osteogenic progenitors, represent the cell of origin for osteosarcoma development. BM-MSC and ASC cultures were established from 3 mouse strains: (a) WT, (b) p53loxP/loxP and (c) p53loxP/loxP RbloxP/loxP. The corresponding mutant cells were generated by excision of the LoxP-flanked sequences by infection of all MSC cultures with adenoviral vectors expressing the Cre-recombinase gene (Ad-CMV-Cre). NSG mice were inoculated subcutaneously with 5×10^6 mutant cells. Animals were killed when tumors reached 1 cm3 or 150 days after infusion. Some of the obtained tumors were mechanically disaggregated to establish ex vivo MSC-transformed cell lines. Gene expression analysis was performed using BM-MSCs and ASCs from all genotypes, as well as tumor cell lines derived from p53-/- and p53-/-Rb-/- BM-MSC and ASC cultures.

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Robust Neurogenesis in Chronic Stroke Monkeys Following Mesenchymal Stem Cell Transplantation Plus Intermittent Theta-burst Stimulation

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