Abstract
This study investigates the effect of bone marrow (BM-MSCs) and visceral peritoneum (VP-MSCs)-derived mesenchymal stem cells on the transplanted ovary. VP-MSCs and BM-MSCs were obtained from green fluorescent protein-expressing mice (GFP+). Six- to eight-week-old female NMRI mice were divided into four experimental groups, autograft ovarian tissue fragments (AO), autograft ovarian tissue fragments encapsulated in fibrin-collagen hydrogel (AO-H), autograft ovarian tissue fragments encapsulated in fibrin-collagen hydrogel containing BM-MSCs (AO-HB) and autograft ovarian tissue fragments encapsulated in fibrin-collagen hydrogel containing VP-MSCs (AO-HP). Intact ovary (IO) was the control group. The estrous cycles resumption time was monitored and at the third estrous cycle, the blood samples and grafted ovaries were evaluated using hormonal, histological and gene expression analysis. Onset of estrous cycles, especially at the second cycle, was earlier in AO-HB and AO-HP groups than in the AO-H group (P < 0.05). Moreover, E2 and FSH levels in AO-HB and AO-HP groups were returned to those of the intact group. However, folliculogenesis was still retarded as compared with the IO group. The gene expression of theca (Lhcgr, Cyp17a1, Gli2, Gli3 and Ptch1), granulosa (Amh and Fshr), oocyte (Zp3 and Gdf9), germ cells (Stella and Prdm1), angiogenesis (VEGF and bFGF) and apoptosis (Bax/Bcl2 and Caspase3) markers was similar in both AO-HB and AO-HP groups. Expression of Amh, Fshr, Gdf9 and VEGF increased only in the AO-HP group whereas expression of Ptch1 increased only in the AO-HB group, as compared with the AO group (P < 0.05). In conclusion, BM-MSCs or VP-MSCs can improve ovarian autotransplantation in mice with no superiority over each other.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abd-Allah SH, Shalaby SM, Pasha HF, Amal S, Raafat N, Shabrawy SM, Awad HA, Amer MG, Gharib MA, El Gendy EA (2013) Mechanistic action of mesenchymal stem cell injection in the treatment of chemically induced ovarian failure in rabbits. Cytotherapy 15:64–75. https://doi.org/10.1016/j.jcyt.2012.08.001
Abir R, Nitke S, Ben-Haroush A, Fisch B (2006) In vitro maturation of human primordial ovarian follicles. Clinical significance, progress in mammals, and methods for growth evaluation. Histol Histopathol 21:887–898. https://doi.org/10.14670/HH-21.887
Akhavan Taheri M, Rezazadeh Valojerdi M, Ebrahimi B (2016) Intramuscular autotransplantation of vitrified rat ovary encapsulated with hyaluronic acid hydrogel. Biopreserv Biobank 14:114–121. https://doi.org/10.1089/bio.2015.0021
Asgari HR, Akbari M, Yazdekhasti H, Rajabi Z, Navid S, Aliakbari F, Abbasi N, Aval FS, Shams A, Abbasi M (2017) Comparison of human amniotic, chorionic, and umbilical cord multipotent mesenchymal stem cells regarding their capacity for differentiation toward female germ cells. Cell Reprogram 19:44–53. https://doi.org/10.1089/cell.2016.0035
Au P, Tam J, Fukumura D, Jain RK (2008) Bone marrow–derived mesenchymal stem cells facilitate engineering of long-lasting functional vasculature. Blood 111:4551–4558. https://doi.org/10.1182/blood-2007-10-118273
Baird A, Hsueh AJ (1986) Fibroblast growth factor as an intraovarian hormone: differential regulation of steroidogenesis by an angiogenic factor. Regul Pept 16:243–250. https://doi.org/10.1016/0167-0115(86)90023-6
Berisha B, Schams D, Rodler D, Pfaffl MW (2016) Angiogenesis in the ovary - the most important regulatory event for follicle and corpus luteum development and function in cow - an overview. Anat Histol Embryol 45:124–130. https://doi.org/10.1111/ahe.12180
Bonvini S, Albiero M, Ferretto L, Angelini A, Battocchio P, Fedrigo M, Piazza M, Thiene G, Avogaro A, Fadini GP (2012) The peritoneum as a natural scaffold for vascular regeneration. PLoS One 7:e33557. https://doi.org/10.1371/journal.pone.0033557
Bukovsky A, Virant-Klun I, Svetlikova M, Willson I (2006) Ovarian germ cells. Methods Enzymol 419:208–258. https://doi.org/10.1016/S0076-6879(06)19010-2
D’andrea F, De Francesco F, Grella R, Ferraro G (2010) Human Cd34/cd90 Ascs are capable of growing as sphere clusters, producing high levels of Vegf and forming capillaries: 1105. Eur J Clin Invest 40:88
Damous LL, Nakamuta JS, Soares-Jr JM, Maciel GAR, dos Santos Simões R, de Souza Montero EF, Krieger JE, Baracat EC (2014) Females transplanted with ovaries subjected to hypoxic preconditioning show impair of ovarian function. J Ovarian Res 7:34. https://doi.org/10.1186/1757-2215-7-34
Damous LL, Nakamuta JS, de Carvalho AES, Carvalho KC, Soares-Jr JM, Simões MJ, Krieger JE, Baracat EC (2015a) Does adipose tissue-derived stem cell therapy improve graft quality in freshly grafted ovaries? Reprod Biol Endocrinol 13:108. https://doi.org/10.1186/s12958-015-0104-2
Damous LL, Nakamuta JS, de Carvalho AE, Soares JM Jr, de Jesus Simões M, Krieger JE, Baracat EC (2015b) Adipose tissue-derived stem cell therapy in rat cryopreserved ovarian grafts. Stem Cell Res Ther 6:57. https://doi.org/10.1186/s13287-015-0068-3
Dissen G, Lara H, Fahrenbach W, Costa M, Ojeda S (1994) Immature rat ovaries become revascularized rapidly after autotransplantation and show a gonadotropin-dependent increase in angiogenic factor gene expression. Endocrinology 134:1146–1154. https://doi.org/10.1210/endo.134.3.8119153
Dolmans MM, Donnez J, Camboni A, Demylle D, Amorim C, Van Langendonckt A, Pirard C (2009) IVF outcome in patients with orthotopically transplanted ovarian tissue. Hum Reprod 24:2778–2787. https://doi.org/10.1093/humrep/dep289
Donnez J, Dolmans MM (2017) Fertility preservation in women. N Engl J Med 377:1657–1665. https://doi.org/10.1056/NEJMra1614676
Donnez J, Dolmans M-M, Demylle D, Jadoul P, Pirard C, Squifflet J, Martinez-Madrid B, Van Langendonckt A (2004) Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet 364:1405–1410. https://doi.org/10.1016/S0140-6736(04)17222-X
Donnez J, Martinez-Madrid B, Jadoul P, Van Langendonckt A, Demylle D, Dolmans M-M (2006) Ovarian tissue cryopreservation and transplantation: a review. Hum Reprod Update 12:519–535. https://doi.org/10.1093/humupd/dml032
Durlinger AL, Kramer P, Karels B, de Jong FH, Uilenbroek JT, Grootegoed JA, Themmen AP (1999) Control of primordial follicle recruitment by anti-Mullerian hormone in the mouse ovary. Endocrinology 140:5789–5796. https://doi.org/10.1210/endo.140.12.7204
Foroutan T, Hosseini A, Pourfatholah A, Soleimani M, Alimoghadam K, Mosaffa NJJB (2010) Peritoneal mesothelial progenitor or stem cell. 10:460–464. https://doi.org/10.3923/jbs.2010.460.464
Fu X, He Y, Xie C, Liu W (2008) Bone marrow mesenchymal stem cell transplantation improves ovarian function and structure in rats with chemotherapy-induced ovarian damage. Cytotherapy 10:353–363. https://doi.org/10.1080/14653240802035926
Gao J, Huang Y, Li M, Zhao H, Zhao Y, Li R, Yan J, Yu Y, Qiao J (2015) Effect of local basic fibroblast growth factor and vascular endothelial growth factor on subcutaneously allotransplanted ovarian tissue in ovariectomized mice. PLoS One 10:e0134035. https://doi.org/10.1371/journal.pone.0134035
Gavish Z, Peer G, Hadassa R, Yoram C, Meirow D (2014) Follicle activation and ‘burn-out’ contribute to post-transplantation follicle loss in ovarian tissue grafts: the effect of graft thickness. Hum Reprod 29:989–996. https://doi.org/10.1093/humrep/deu015
Honda A, Hirose M, Hara K, Matoba S, Inoue K, Miki H, Hiura H, Kanatsu-Shinohara M, Kanai Y, Kono T (2007) Isolation, characterization, and in vitro and in vivo differentiation of putative thecal stem cells. Proc Natl Acad Sci U S A 104:12389–12394. https://doi.org/10.1073/pnas.0703787104
Hsiao ST, Asgari A, Lokmic Z, Sinclair R, Dusting GJ, Lim SY, Dilley RJ (2011) Comparative analysis of paracrine factor expression in human adult mesenchymal stem cells derived from bone marrow, adipose, and dermal tissue. Stem Cells Dev 21:2189–2203. https://doi.org/10.1089/scd.2011.0674
Huang SD, Lu FL, Xu XY, Liu XH, Zhao XX, Zhao BZ, Wang L, Gong DJ, Yuan Y, Xu ZY (2006) Transplantation of angiogenin-overexpressing mesenchymal stem cells synergistically augments cardiac function in a porcine model of chronic ischemia. J Thorac Cardiovasc Surg 132:1329–1338. https://doi.org/10.1016/j.jtcvs.2006.08.021
Huang P, Lin LM, Wu XY, Tang QL, Feng XY, Lin GY, Lin X, Wang HW, Huang TH, Ma L (2010) Differentiation of human umbilical cord Wharton's jelly-derived mesenchymal stem cells into germ-like cells in vitro. J Cell Biochem 109:747–754. https://doi.org/10.1002/jcb.22453
Israely T, Nevo N, Harmelin A, Neeman M, Tsafriri A (2006) Reducing ischaemic damage in rodent ovarian xenografts transplanted into granulation tissue. Hum Reprod 21:1368–1379. https://doi.org/10.1093/humrep/del010
Jalili RB, Moeen Rezakhanlou A, Hosseini-Tabatabaei A, Ao Z, Warnock GL, Ghahary A (2011) Fibroblast populated collagen matrix promotes islet survival and reduces the number of islets required for diabetes reversal. J Cell Physiol 226:1813–1819. https://doi.org/10.1002/jcp.22515
Karp JM, Teo GSL (2009) Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell 4:206–216. https://doi.org/10.1016/j.stem.2009.02.001
Keshteli FZR, Parivar K, Joghatayi MT, Beik HA (2013) Study of the differentiation of rat omentum stem cells to nerve cells using brain tissue extract of Wistar rats. Int J Cell Biol Mol Biotech 2014:1–13. https://doi.org/10.5899/2014/ijcmb-00009
Lavranos TC, Rodgers HF, Bertoncello I, Rodgers RJ (1994) Anchorage-independent culture of bovine granulosa cells: the effects of basic fibroblast growth factor and dibutyryl cAMP on cell division and differentiation. Exp Cell Res 211:245–251. https://doi.org/10.1006/excr.1994.1084
Liu XH, Bai CG, Xu ZY, Huang SD, Yuan Y, Gong DJ, Zhang JR (2008) Therapeutic potential of angiogenin modified mesenchymal stem cells: angiogenin improves mesenchymal stem cells survival under hypoxia and enhances vasculogenesis in myocardial infarction. Microvasc Res 76:23–30. https://doi.org/10.1016/j.mvr.2008.02.005
Manavella D, Cacciottola L, Desmet C, Jordan B, Donnez J, Amorim C, Dolmans MM (2018) Adipose tissue-derived stem cells in a fibrin implant enhance neovascularization in a peritoneal grafting site: a potential way to improve ovarian tissue transplantation. Hum Reprod 33:270–279. https://doi.org/10.1093/humrep/dex374
Mattioli M, Barboni B, Turriani M, Galeati G, Zannoni A, Castellani G, Berardinelli P, Scapolo PA (2001) Follicle activation involves vascular endothelial growth factor production and increased blood vessel extension. Biol Reprod 65:1014–1019. https://doi.org/10.1095/biolreprod65.4.1014
Meirow D, Levron J, Eldar-Geva T, Hardan I, Fridman E, Yemini Z, Dor J (2007) Monitoring the ovaries after autotransplantation of cryopreserved ovarian tissue: endocrine studies, in vitro fertilization cycles, and live birth. Fertil Steril 87:418. e417–418. e415. https://doi.org/10.1016/j.fertnstert.2006.05.086
Mendel TA, Clabough EB, Kao DS, Demidova-Rice TN, Durham JT, Zotter BC, Seaman SA, Cronk SM, Rakoczy EP, Katz AJ (2013) Pericytes derived from adipose-derived stem cells protect against retinal vasculopathy. PLoS One 8:e65691. https://doi.org/10.1371/journal.pone.0065691
Mirzaeian L, Eftekhari-Yazdi P, Esfandiari F, Eivazkhani F, Rezazadeh Valojerdi M, Moini A, Fathi R (2019) Induction of mouse peritoneum mesenchymal stem cells into germ cell-like cells using follicular fluid and cumulus cells conditioned media. Stem Cells Dev 28:554–564. https://doi.org/10.1089/scd.2018.0149
Nadri S, Soleimani M, Hosseni RH, Massumi M, Atashi A, Izadpanah R (2002) An efficient method for isolation of murine bone marrow mesenchymal stem cells. Int J Dev Biol 51:723–729. https://doi.org/10.1387/ijdb.072352ns
Nakamuta JS, Danoviz ME, Marques FL, Dos Santos L, Becker C, Gonçalves GA, Vassallo PF, Schettert IT, Tucci PJ, Krieger JE (2009) Cell therapy attenuates cardiac dysfunction post myocardial infarction: effect of timing, routes of injection and a fibrin scaffold. PLoS One 4:e6005. https://doi.org/10.1371/journal.pone.0006005
Patel DM, Shah J, Srivastava AS (2013) Therapeutic potential of mesenchymal stem cells in regenerative medicine. Stem Cells Int 2013:496218. https://doi.org/10.1155/2013/496218
Qiu P, Bai Y, Pan S, Li W, Liu W, Hua J (2013) Gender depended potentiality of differentiation of human umbilical cord mesenchymal stem cells into oocyte-like cells in vitro. Cell Biochem Funct 31:365–373. https://doi.org/10.1002/cbf.2981
Roubelakis MG, Tsaknakis G, Pappa KI, Anagnou NP, Watt SM (2013) Spindle shaped human mesenchymal stem/stromal cells from amniotic fluid promote neovascularization. PLoS One 8:e54747. https://doi.org/10.1371/journal.pone.0054747
Sarvandi SS, Joghataei MT, Parivar K, Khosravi M, Sarveazad A, Sanadgol N (2015) In vitro differentiation of rat mesenchymal stem cells to hepatocyte lineage. Iran J Basic Med Sci 18:89–97
Sassoli C, Pini A, Chellini F, Mazzanti B, Nistri S, Nosi D, Saccardi R, Quercioli F, Zecchi-Orlandini S, Formigli L (2012) Bone marrow mesenchymal stromal cells stimulate skeletal myoblast proliferation through the paracrine release of VEGF. Sassoli C 7:e37512. https://doi.org/10.1371/journal.pone.0037512
Schubert B, Canis M, Darcha C, Artonne C, Smitz J, Grizard G (2008) Follicular growth and estradiol follow-up after subcutaneous xenografting of fresh and cryopreserved human ovarian tissue. Fertil Steril 89:1787–1794. https://doi.org/10.1016/j.fertnstert.2007.03.101
Shikanov A, Zhang Z, Xu M, Smith RM, Rajan A, Woodruff TK, Shea LD (2011) Fibrin encapsulation and vascular endothelial growth factor delivery promotes ovarian graft survival in mice. Tissue Eng Part A 17:3095–3104. https://doi.org/10.1089/ten.TEA.2011.0204
Shojafar E, Mehranjani MS, Shariatzadeh SMA (2018) Adipose-derived mesenchymal stromal cell transplantation at the graft site improves the structure and function of autografted mice ovaries: a stereological and biochemical analysis. Cytotherapy 20:1324–1336. https://doi.org/10.1016/j.jcyt.2018.09.006
Silvestris E, D’Oronzo S, Cafforio P, D’Amato G, Loverro G (2015) Perspective in infertility: the ovarian stem cells. J Ovarian Res 8:55. https://doi.org/10.1186/s13048-015-0184-9
Spees JL, Lee RH, Gregory CA (2016) Mechanisms of mesenchymal stem/stromal cell function. Stem Cell Res Ther 7:125. https://doi.org/10.1186/s13287-016-0363-7
Spicer LJ, Echternkamp SE, Wong EA, Hamilton DT, Vernon RK (1995) Serum hormones, follicular fluid steroids, insulin-like growth factors and their binding proteins, and ovarian IGF mRNA in sheep with different ovulation rates. J Anim Sci 73:1152–1163. https://doi.org/10.2527/1995.7341152x
Sugiura K, Su YQ, Diaz FJ, Pangas SA, Sharma S, Wigglesworth K, O'Brien MJ, Matzuk MM, Shimasaki S, Eppig J (2007) Oocyte-derived BMP15 and FGFs cooperate to promote glycolysis in cumulus cells. Development 134:2593–2603. https://doi.org/10.1242/dev.006882
Sun M, Wang S, Li Y, Yu L, Gu F, Wang C, Yao Y (2013) Adipose-derived stem cells improved mouse ovary function after chemotherapy-induced ovary failure. Stem Cell Res Ther 4:80. https://doi.org/10.1186/scrt231
Tao H, Han Z, Han ZC, Li Z (2016) Proangiogenic features of mesenchymal stem cells and their therapeutic applications. Stem Cells Int 2016:1314709. https://doi.org/10.1155/2016/1314709
Tavana S, Azarnia M, Valojerdi MR, Shahverdi A (2016a) Hyaluronic acid-based hydrogel scaffold without angiogenic growth factors enhances ovarian tissue function after autotransplantation in rats. Biomed Mater 11:055006. https://doi.org/10.1088/1748-6041/11/5/055006
Tavana S, Valojerdi MR, Azarnia M, Shahverdi A (2016b) Restoration of ovarian tissue function and estrous cycle in rat after autotransplantation using hyaluronic acid hydrogel scaffold containing VEGF and bFGF. Growth Factors 34:97–106. https://doi.org/10.1080/08977194.2016.1194835
Truman AM, Tilly JL, Woods DC (2017) Ovarian regeneration: the potential for stem cell contribution in the postnatal ovary to sustained endocrine function. Mol Cell Endocrinol 445:74–84. https://doi.org/10.1016/j.mce.2016.10.012
Vernon R, Spicer LJ (1994) Effects of basic fibroblast growth factor and heparin on follicle-stimulating hormone-induced steroidogenesis by bovine granulosa cells. J Anim Sci 72:2696–2702. https://doi.org/10.2527/1994.72102696x
Volarevic V, Arsenijevic N, Lukic ML, Stojkovic M (2011) Concise review: mesenchymal stem cell treatment of the complications of diabetes mellitus. Stem Cells 29:5–10. https://doi.org/10.1002/stem.556
Xia X, Yin T, Yan J, Yan L, Jin C, Lu C, Wang T, Zhu X, Zhi X, Wang J (2014) Mesenchymal stem cells enhance angiogenesis and follicle survival in human cryopreserved ovarian cortex transplantation. Cell Transplant 24:1999–2010. https://doi.org/10.3727/096368914X685267
Yang G, Alvarez II (1995) Ultrafast Papanicolaou stain. An alternative preparation for fine needle aspiration cytology. Acta Cytol 39:55–60
Yang H, Lee HH, Lee HC, Ko DS, Kim SS (2008) Assessment of vascular endothelial growth factor expression and apoptosis in the ovarian graft: can exogenous gonadotropin promote angiogenesis after ovarian transplantation? 90:1550–1558. https://doi.org/10.1016/j.fertnstert.2007.08.086
Ye Q, Zünd G, Benedikt P, Jockenhoevel S, Hoerstrup SP, Sakyama S, Hubbell JA, Turina M (2000) Fibrin gel as a three dimensional matrix in cardiovascular tissue engineering. Eur J Cardiothorac Surg 17:587–591. https://doi.org/10.1016/s1010-7940(00)00373-0
Zhang Y, Xia X, Yan J, Yan L, Lu C, Zhu X, Wang T, Yin T, Li R, Chang H-M (2017) Mesenchymal stem cell-derived angiogenin promotes primodial follicle survival and angiogenesis in transplanted human ovarian tissue. Reprod Biol Endocrinol 15:18. https://doi.org/10.1186/s12958-017-0235-8
Zhao L, Johnson T, Liu D (2017) Therapeutic angiogenesis of adipose-derived stem cells for ischemic diseases. Stem Cell Res Ther 8:125. https://doi.org/10.1186/s13287-017-0578-2
Acknowledgments
We thank Dr. Azam Dalman for her assistance in preparation of the manuscript and Dr. Saman Maroufizadeh for statistical analysis.
Funding
This study was financially supported by the Iran University of Medical Sciences (grant number: 27891) and Royan Institute (grant number: 95000259).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
The experiment was approbated by the local Ethics Committee (IR.ACECR ROYAN.REC.1396.21) on the Utilization and Care of Animals.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Mehdinia, Z., Ashrafi, M., Fathi, R. et al. Restoration of estrous cycles by co-transplantation of mouse ovarian tissue with MSCs. Cell Tissue Res 381, 509–525 (2020). https://doi.org/10.1007/s00441-020-03204-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00441-020-03204-x