Table 2.

Preclinical studies of MSCs in the treatment of OI

Cell Type	Model	Type of OI	Methods	Results	Reference
Murine Cells or Cell Products into Mice
Allogeneic BMSCs from WT mice	Transgenic mice, 3 week old, irradiated	I	IP	• Low engraftment @ 1 mo • Differentiate into fibroblasts in multiple tissues @ 2.5 mo • Continual source of new cells • Only small effects on bone phenotype @ 1 mo • Increased collagen and mineral content @ 1 mo	Semler et al. 2012
Allogeneic BMSCs from WT mice	oim mice, 8-10 week old, irradiated	III	IO	• Robust engraftment @ 1 mo • Long term engraftment @ 3 and 6 mo • Differentiation into osteoblasts @ 3 mo • Continual source of new cells @ 6 mo • Improved cortical structure and strength @ 3 and 6 mo	Strube et al. 2009
Allogeneic BMSCs from WT mice	BrtIIV mice, E13.5-14.5	III/IV	IUT	• Eliminated perinatal lethality All results measured @ 2 mo of age • Low engraftment • Differentiated into functional osteoblasts • Improved bone mechanics • Improved mineralization and cortical thickness	Théry et al. 2009
Genetically modified ASCs from WT mice	COL1A1 knockout, 8 week old males	I	IV	All results measured @ 4 weeks after treatment • Genetically modified ASCs migrated to femur • Genetically modified ASCs differentiated into bone cells • ASCs improved cortical structure and thickness Further improvements when combined with Nell1 Most improvement when genetically modified with NELL1	Thiele et al. 2012
ASCs from WT mice, OI mice, and OI mice with genetic modification	COL1A1 knockout, 8 week old males	I	IO	All results measured @ 4 weeks after treatment • Cells migrated to femur • Cells differentiated into osteoblasts • Promoted bone formation • ASCs from WT mice improved bone structure, thickness, and mechanical properties • Genetically modified ASCs from OI mice improved all above but not as much • ASCs from OI mice were not therapeutic	Shapiro et al. 2013
BMSC-derived EVs from WT mice	G610C knock in, 3 weeks old	I of IV	IV once / week, for 4 weeks	All results measured @ 2 weeks after last treatment (@ 2 mo of age) • Increased bone growth • miRNA depletion in EVs removed therapeutic effects	Pereira et al. 1995
Human Cells into Mice
Human fMSCs, 10 week old fetus 1 donor	oim mice, E13.5-E15	III	IUT	• Donor cells persisted in numerous tissues @ 3 mo of age More cells found at 1 week of age than 3 mo of age Retention was greater in bone (5% engraftment) • Donor cells accumulated in areas of active bone formation, remodeling, and fracture sites • Remained as progenitors in bone marrow but differentiated into osteoblasts in bone • Improved bone mechanics @ 1, 2, and 3 mo after birth • Reduced fractures @ 1, 2, and 3 mo after birth	Mäyränpää et al. 2011
Human fMSCs, 10 week old fetus 1 donor	oim mice, E13.5-E15	III	IUT	All results measured @ 2 mo of age • Significant reduction in femoral fractures • Donor cells engrafted in bone (5%) • Differentiated into functional osteoblasts, expressed osteocalcin • Increased matrix stiffness • No changes in bone morphology	Mazini et al. 2019
Human fMSCs, 10-12 week old fetus, primed with SDF-1	oim mice, 2-3 day old neonates	III	IP	All results measured @ 2 mo of age, compared to unprimed cells • Increased migration to bone and bone marrow • Higher engraftment in bone and bone marrow • More therapeutic benefit • Reduced fractures	Valadares et al. 2014
Human CSC, 9-10 week old fetus	oim mice, 2-3 day old neonates	III	IP	All results measured @ 2 mo of age • Less fractures • Increased bone ductility and volume • did not affect bone length or cortical bone formation • Decreased bone brittleness • Differentiated into functional osteoblasts • Upregulated endogenous genes for ossifications • Homed to epiphysis of long bones	L. et al. 2019
Genetically modified BMSCs from OI patient	NOD/SCID, 2-3 month old	NA	SD	All results measured @ 2 mo of age • In vivo bone formation • Increased collagen processing, stability, and structure	Khillan et al. 1991

Abbreviations: mo month/months, EVs Extracellular vesicles, IO Intraosseous, IV Intravenous, IP Intraperitoneal, IUT In utero transplantation, SD Sub-dermal transplant, NA Not addressed, WT Wild type