Table 1.

Role of Estrogens on Bone Marrow-Derived Stromal Cell Stemness

Cell type	Bone marrow derived stromal cells
	Sex	Animal model, age	In vitro, in vivo	Hormone treatment	Response	Study
Mouse cells
BM-MSCs	F and M	C57 mice, 8-week old	In vitro	None	After stress by LPS treatment or hypoxia: F: increased VEGF compared to M M: increased TNF and IL-6 compared to F; hypoxia induced more apoptosis compared to F	Crisostomo et al.12
BM-MSCs	F and M	BALB/c mice of different ages	In vitro	None	F and M: higher passages decreased adipogenic potential and increased osteogenic potential M: greater potential toward both adipogenic and osteogenic lineages compared to F	Katsara et al.22
BM-MSCs	F	C57/BL6 mice, 8-week old	In vitro	ovx	ovx: increased adipogenic markers; decreased osteogenic markers	Qi et al.31
BM-MSCs	F	Swiss-Webster mice, 7-month old	In vitro	10−10–10−6 M E2; ovx	E2 treatment: increased proliferation and differentiation to osteoblasts; decreased apoptosis; increased the expression of ERα; decreased the expression of ERβ ovx: proliferation and differentiation were lower than in cells from sham mice; apoptosis was higher.	Zhou et al.29
Bone marrow-derived stroma cell line ST2 stably overexpressing human ERα or ERβ	N/A	Mouse, age N/A	In vitro	0–1 nM E2	Cotreatment of cells with estrogen and (BMP)-2: increased osteogenesis compared to cells treated with just BMP-2 Treatment with E2: decreased adipogenesis	Okazaki et al.33
BM-MSCs	N/A	C57BL/6 mice, age N/A	In vitro	10 nM E2	E2 treatment: increased osteogenesis	Pang et al.32
BM-MSCs	F	C57BL/6 mice, 8-week old	In vitro	10−7 M E2; ovx	ovx mice: BM-MSCs more senescent, less proliferative, and lower osteogenic potential than those from sham animals; these deficiencies were alleviated by E2 treatment; effects linked to the JAK2/STAT3 pathway.	Wu et al.30
Rat cells
BM-MSCs	F and M	Sprague-Dawley rats, 12-month old	In vitro	None	No sex related differences in proliferation, differentiation, or senescence F: fewer BM-MSCs compared to M M: MSCs showed superior healing compared to F	Strube et al.23
BM-MSCs	F	Sprague-Dawley rats, 12-week old	In vitro	ovx	ovx: reduced pluripotency and increased senescence through ERβ-SATB2	Wu et al.34
BM-MSCs	F and M	F-344 rats, 3-month old	In vitro	10−6–10−12 M E2	E2 treatment: F: lower concentrations increased proliferation rate and osteogenic potential M: no change in proliferation rate; increased osteogenic potential	Hong et al.36
BM-MSCs	F	Sprague-Dawley rats, 9-week old	In vitro	10−7 M E2; ovx	E2 treatment: increased colony numbers and number of cells per colony of cells; no effect on osteogenic potential; decreased adipogenic potential; decreased apoptosis	Ayaloglu-Butun et al.35
BM-MSCs	F	Sprague-Dawley rats, 8-week old	In vitro	1 nM E2	E2 treatment: increased number of cells in the S-phase; increased osteogenic differentiation; decreased chondrogenesis activated MAPK pathway	Zhao et al.37
BM-MSCs	M	Sprague-Dawley rats, 4-week old	In vitro	0, 1, 10, 100, 500, 1000 nM E2	E2 treatment: no effect on viability; dose-dependent increases in osteogenesis.	Liu et al.38
Larger animal cells
BM-MSCs	F and M	Mini-pig, 1-year old	In vitro	0, 10−6, 10−8, 10−10, 10−10, 10−12, 10−14 M E2	E2 treatment: reduced apoptosis-related gene expression and increased chondrogenesis in both sexes F: proliferation rates increased with decreasing concentration; increased osteogenic differentiation; decreased adipogenic differentiation M: lower concentrations increased proliferation while higher concentrations decreased proliferation; increased adipogenic differentiation	Lee et al.39
BM-MSCs	M	Beagle dogs, sexually mature	In vitro	0, 10−7, 10−9, 10−11, 10−13, 10−15 M E2	E2 treatment: Above 10−11 M: inhibited proliferation and increased apoptosis 10−11 M: increased proliferation; decreased apoptosis; no effect on osteogenesis or adipogenesis.	Zhou et al.40
Human cells
BM-MSCs	F	Human, 41–51-year old, perimenopausal	In vitro	10 nM E2	Osteogenic differentiation: ERα and ERβ expression increased Adipogenic differentiation: ERα expression increased; ERβ unchanged E2 treatment: increased osteogenesis; decreased adipogenesis	Heim et al.48
BM-MSCs	M	Human, 40–44-year old	In vitro	1, 2, 4, 8, 10, 50, 100 nM E2	E2 treatment: increased osteoblast proliferation in a dose dependent manner between 1 and 8 nM, with no further increase seen at higher concentrations; 1 and 2 nM E2 increased proliferation, but higher doses had no effect.	DiSilvio et al.41
BM-MSCs	M	Human, adult	In vitro	10 nM, 10 pM E2	E2 treatment + osteogenic stimulation: enhanced osteogenic potential; no change in proliferation E2 treatment + adipogenic stimulation: increased adipogenic potential, decreased proliferation	Hong et al.45
BM-MSCs	M	Human, 18–45-year old	In vitro	10−11–10−8 M E2	E2 treatment: no effect on proliferation; inhibited chondrogenesis	Jenei-Lanzl et al.44
BM-MSCs	M	Human, 31–62-year old	In vitro	10−7, 10−9, 10−11 M E2	E2 treatment: no effect on cell proliferation rate, time to senescence, or the expression of telomere and senescence-associated genes; decreased telomere shortening over time	Breu et al.43
BM-MSCs	F and M	Human, 27.4 ± 6.1-year old	In vitro	10−6–10−12 M E2	E2 treatment: increased proliferation in both sexes; maintained proliferation rates through more passages than control cells; increased ERα expression; ERβ expression unchanged.	Hong et al.42
BM-MSCs	F	Human, age N/A	In vitro	100 pM–1 mM E2	E2 treatment: increased osteogenic and adipogenic potential	Strong et al.47
BM-MSCs	N/A (lot specific)	Human, age N/A (lot specific)	In vitro	1 nM E2	E2 treatment: upregulated expression of components of autophagosome genes; increased autophagic flux	Gavali et al.46

BM-MSC, bone marrow-derived mesenchymal stromal cell; BMP-2, bone morphogenetic protein 2; E2, 17β-estradiol; ERα, estrogen receptor α; ERβ, estrogen receptor β; F, female; IL-6, interleukin 6; LPS, lipopolysaccharide; M, male; MAPK, mitogen-activated protein kinase; N/A, not available; ovx, ovariectomized; TNF, tumor necrosis factor; SATB2, sequence binding protein 2; VEGF, vascular endothelial growth factor.