Table 2 Preclinical studies of MSCs in the treatment of OI

  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 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