Skip to main content

Advertisement

SpringerLink
Log in

Role and Mechanism of BMP4 in Regenerative Medicine and Tissue Engineering

  • Review
  • Published:
Annals of Biomedical Engineering Aims and scope Submit manuscript

Abstract

Bone morphogenetic protein 4 (BMP4) is emerging as a promising cytokine for regenerative medicine and tissue engineering. BMP4 has been shown to promote the regeneration of teeth, periodontal tissue, bone, cartilage, the thymus, hair, neurons, nucleus pulposus, and adipose tissue, as well as the formation of skeletal myotubes and vessels. BMP4 can also contribute to the formation of tissues in the heart, lung, and kidney. However, there are certain deficiencies, including the insufficiency of the mechanism of BMP4 in some fields and an appropriate carrier of BMP4 for clinical use. There has also been a lack of in vivo experiments and orthotopic transplantation studies in some fields. BMP4 has great distance from the clinical application. Therefore, there are many BMP4-related studies waiting to be explored. This review mainly discusses the effects, mechanisms, and applications of BMP4 in regenerative medicine and tissue engineering over the last 10 years in various domains and possible improvements. BMP4 has shown great potential in regenerative medicine and tissue engineering. The research of BMP4 has broad development space and great value.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

Abbreviations

AAV-BMP4:

Adeno-associated virus containing BMP4 gene

ADSCs:

Adipose-derived stem cells

Ad-BMP4:

Adenovirus expressing BMP4

ALK2:

Activin receptor-like kinase 2

ALP:

Alkaline phosphatase

AMBN:

Ameloblastin

AP:

Alkaline phosphatase

ASF:

Ameloblasts serum-free

ASF-CM:

Ameloblasts serum-free conditioned medium

bFGF:

Basic fibroblast growth factor

BMP4:

Bone morphogenetic protein 4

BMP7:

Bone morphogenetic protein 7

BMPs:

Bone morphogenetic proteins

BMPR:

Bone morphogenetic protein receptor

BSP:

Bone sialoprotein

CBD:

Collagen-binding domain

CBFA1:

Core-binding factor alpha 1

cDNA:

Complementary DNA

DE:

Dental epithelium

dECM:

Decellularized dental pulp extracellular matrix

DEC:

Dental epithelial cell

DFAT cells:

De-differentiated fat cells

DFSCs:

Dental follicle stem cells

Dll4:

Delta-like 4

DMP1:

Dentin matrix protein 1

DMSCs:

Dental mesenchyme stem cells

DPCs:

Dental pulp cells

DPSC:

Dental pulp stromal cells

DSP:

Dentin sialoprotein

DSPP:

Dentin sialophosphoprotein

E4ORF1:

Early gene 4 open reading frame-1

EB:

Embryoid bodies

ECs:

Endothelial cells

EGF:

Epidermal growth factor

EGFP:

Enhanced green fluorescent protein

Epi-SCs:

Epidermal stem cells

ERK1/2:

Extracellular regulated protein kinase 1/2

ESCs:

Embryonic stem cells

FGF:

Fibroblast growth factor

FVC:

Fluorenylmethyloxycarbonyl protected Valyl-cetylamide

GAM:

Gene-activated matrix

GFP:

Green fluorescent protein

GSK3β:

Glycogen synthase kinase 3β

HAp:

hydroxyapatite

HFAP:

Hair follicle-associated pluripotent

hASCs:

Human adipose-derived stem cells

hDPCs:

Human dental pulp cells

hESCs:

Human embryonic stem cells

hGF:

Human gingival fibroblasts

hiPSCs:

Human induced pluripotent stem cells

hMDSCs:

Human muscle-derived stem cells

hPSCs:

Human pluripotent stem cells

iNCLCs:

IPS cell-derived neural crest-like cells

iPSCs:

Induced pluripotent stem cells

MDCs:

Muscle-derived cells

MDSCs:

Muscle-derived stem cells

mESCs:

Mouse embryonic stem cells

MMSCs:

Murine mesenchymal stem cells

Myf5:

Myogenic factor 5

NELL-1:

Nerve epidermal growth factor-like 1

NP:

Nucleus pulposus

ntECs:

Non-thymic endothelial cells

OE:

Oral ectoderm

OPN:

Osteopontin

OSM:

Oncostatin M

P38 MAPK:

P38 mitogen-activated protein kinase

PBM:

Photobiomodulation

PCL:

Polycaprolactone

PDGF:

Platelet-derived growth factor

PDGFR:

Platelet-derived growth factor receptor

PDLCs:

Periodontal ligament cells

PEG:

Poly (ethylene glycol)

PGE2:

Prostaglandin E2

PI3-K:

Phosphoinositide 3-kinase

PLGA:

Poly (lactic-co-glycolic acid)

PLLGA:

Poly (L-lactic-co-glycolic acid)

RA:

Retinoic acid

RGC:

Retinal ganglion cells

rhBMP4:

Recombinant human BMP4

rhBMP4-CM:

Recombinant human BMP4-conditioned medium

Runx2:

Runt-related transcription factor 2

R-Smads:

Receptor-regulated Smads

SC:

Subcutaneous

SG:

Sebaceous glands

SKPs:

Skin-derived precursors

Smads:

Drosophila mothers against decapentaplegic proteins

SMCs:

Smooth muscle cells

TGF-β:

Transforming growth factor beta

Trb3:

Tribbles-like protein 3

VEGF:

Vascular endothelial growth factor

vSMC:

Vascular smooth muscle cells

vWF:

Von Willebrand factor

WAT:

White adipose tissue

References

  1. Bai, H., Y. X. Gao, M. Arzigian, D. M. Wojchowski, W. S. Wu, and Z. Z. Wang. BMP4 regulates vascular progenitor development in human embryonic stem cells through a Smad-dependent pathway. J. Cell. Biochem. 109(2):363–374, 2010

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Bleul, C. C., and T. Boehm. BMP signaling is required for normal thymus development. J. Immunol. 175(8):5213–5221, 2005

    Article  CAS  PubMed  Google Scholar 

  3. Boteanu, R. M., V. I. Suica, L. Ivan, F. Safciuc, E. Uyy, E. Dragan, S. M. Croitoru, V. Grumezescu, M. Chiritoiu, L. E. Sima, C. Vlagioiu, G. Socol, and F. Antohe. Proteomics of regenerated tissue in response to a titanium implant with a bioactive surface in a rat tibial defect model. Sci. Rep. 10(1):18493, 2020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Carreira, A. C., G. G. Alves, W. F. Zambuzzi, M. C. Sogayar, and J. M. Granjeiro. Bone morphogenetic proteins: structure, biological function and therapeutic applications. Arch. Biochem. Biophys. 561:64–73, 2014

    Article  CAS  PubMed  Google Scholar 

  5. Chen, D., M. Zhao, and G. R. Mundy. Bone morphogenetic proteins. Growth Factors. 22(4):233–241, 2004

    Article  CAS  PubMed  Google Scholar 

  6. Chen, J., L. J. Liao, T. T. Lana, Z. J. Zhang, K. Gai, Y. B. Huang, J. L. Chen, W. D. Tian, and W. H. Guo. Treated dentin matrix-based scaffolds carrying TGF-β1/BMP4 for functional bio-root regeneration. Appl. Mater. Today.20:100742, 2020

    Article  Google Scholar 

  7. Chen, L. X., Y. Y. Shi, X. Zhang, X. Q. Hu, Z. X. Shao, L. H. Dai, X. D. Ju, Y. F. Ao, and J. Q. Wang. CaAlg hydrogel containing bone morphogenetic protein 4-enhanced adipose-derived stem cells combined with osteochondral mosaicplasty facilitated the repair of large osteochondral defects. Knee Surg. Sports Traumatol. Arthrosc. 27(11):3668–3678, 2019

    Article  PubMed  Google Scholar 

  8. Cheng, L., M. Xie, W. Qiao, Y. Song, Y. Zhang, Y. Geng, W. Xu, L. Wang, Z. Wang, K. Huang, N. Dong, and Y. Sun. Generation and characterization of cardiac valve endothelial-like cells from human pluripotent stem cells. Commun. Biol. 4(1):1039, 2021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chira, S., C. S. Jackson, I. Oprea, F. Ozturk, M. S. Pepper, I. Diaconu, C. Braicu, L. Z. Raduly, G. A. Calin, and I. Berindan-Neagoe. Progresses towards safe and efficient gene therapy vectors. OncoTarget. 6(31):30675–30703, 2015

    Article  PubMed  PubMed Central  Google Scholar 

  10. Cimetta, E., D. Sirabella, K. Yeager, K. Davidson, J. Simon, R. T. Moon, and G. Vunjak-Novakovic. Microfluidic bioreactor for dynamic regulation of early mesodermal commitment in human pluripotent stem cells. Lab Chip. 13(3):355–364, 2013

    Article  CAS  PubMed  Google Scholar 

  11. Cimetta, E., and G. Vunjak-Novakovic. Microscale technologies for regulating human stem cell differentiation. Exp. Biol. Med. 239(9):1255–1263, 2014

    Article  Google Scholar 

  12. Diniz, I. M. A., A. C. O. Carreira, C. R. Sipert, C. M. Uehara, M. S. N. Moreira, L. Freire, C. Pelissari, P. M. Kossugue, D. R. de Araujo, M. C. Sogayar, and M. M. Marques. Photobiomodulation of mesenchymal stem cells encapsulated in an injectable rhBMP4-loaded hydrogel directs hard tissue bioengineering. J. Cell. Physiol. 233(6):4907–4918, 2018

    Article  CAS  PubMed  Google Scholar 

  13. Dudakov, J., M. Van Den Brink, and T. Wertheimer. Use of BMP4 for thymic regeneration. US Patent 10619134, 14 April 2020.

  14. Ferra-Canellas, M. D., M. Munar-Bestard, L. Garcia-Sureda, B. Lejeune, J. M. Ramis, and M. Monjo. BMP4 micro-immunotherapy increases collagen deposition and reduces PGE2 release in human gingival fibroblasts and increases tissue viability of engineered 3D gingiva under inflammatory conditions. J. Periodontol. 92(10):1448–1459, 2021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ferreira, C. L., F. A. M. de Abreu, G. A. B. Silva, F. F. Silveira, L. B. A. Barreto, T. D. Paulino, M. N. Miziara, and J. B. Alves. TGF-beta 1 and BMP-4 carried by liposomes enhance the healing process in alveolar bone. Arch. Oral Biol. 58(6):646–656, 2013

    Article  CAS  PubMed  Google Scholar 

  16. Finnegan, P. W., D. J. Nolan, K. Kucharova, M. D. Ginsberg, and K. N. Wills. Enhancing thymic regeneration for treating and preventing immunodeficiency, involves administering effective amount of therapeutic composition comprising engineered non-thymic endothelial cells to subject in need of thymic regeneration. US Patent, WO2020243310-A1, 28 May 2020.

  17. Frank, N. Y., A. T. Kho, T. Schatton, G. F. Murphy, M. J. Molloy, Q. Zhan, M. F. Ramoni, M. H. Frank, I. S. Kohane, and E. Gussoni. Regulation of myogenic progenitor proliferation in human fetal skeletal muscle by BMP4 and its antagonist Gremlin. J. Cell Biol. 175(1):99–110, 2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gao, X. Q., A. Usas, A. P. Lu, Y. Tang, B. Wang, C. W. Chen, H. S. Li, J. C. Tebbets, J. H. Cummins, and J. Huard. BMP2 is superior to BMP4 for promoting human muscle-derived stem cell-mediated bone regeneration in a critical-sized calvarial defect model. Cell Transplant. 22(12):2393–2408, 2013

    Article  PubMed  Google Scholar 

  19. Gao, X. Q., A. Usas, J. D. Proto, A. P. Lu, J. H. Cummins, A. Proctor, C. W. Chen, and J. Huard. Role of donor and host cells in muscle-derived stem cell-mediated bone repair: differentiation vs. paracrine effects. FASEB J. 28(8):3792–3809, 2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gherasim, O., A. M. Grumezescu, V. Grumezescu, E. Andronescu, I. Negut, A. C. Birca, B. Galateanu, and A. Hudita. Bioactive coatings loaded with osteogenic protein for metallic implants. Polymers (Basel). 13(24):4303, 2021

    Article  CAS  PubMed  Google Scholar 

  21. Guadix, J. A., V. V. Orlova, E. Giacomelli, M. Bellin, M. C. Ribeiro, C. L. Mummery, J. M. Perez-Pomares, and R. Passier. Human pluripotent stem cell differentiation into functional epicardial progenitor cells. Stem Cell Rep. 9(6):1754–1764, 2017

    Article  CAS  Google Scholar 

  22. Hara, M., Y. Sumita, Y. Kodama, M. Iwatake, H. Yamamoto, R. Shido, S. Narahara, T. Ogaeri, H. Sasaki, and I. Asahina. Gene-activated matrix with self-assembly anionic nano-device containing plasmid DNAs for rat cranial bone augmentation. Materials. 14(22):7097, 2021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Heldin, C. H., K. Miyazono, and P. tenDijke. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 390(6659):465–471, 1997

    Article  CAS  PubMed  Google Scholar 

  24. Hogan, B. L. M. Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev. 10(13):1580–1594, 1996

    Article  CAS  PubMed  Google Scholar 

  25. Holladay, C. A., T. O’Brien, and A. Pandit. Non-viral gene therapy for myocardial engineering. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2(3):232–248, 2010

    Article  CAS  PubMed  Google Scholar 

  26. Huang, P., T. J. Schulz, A. Beauvais, Y. H. Tseng, and E. Gussoni. Intramuscular adipogenesis is inhibited by myo-endothelial progenitors with functioning Bmpr1a signalling. Nat. Commun. 5:4063, 2014

    Article  CAS  PubMed  Google Scholar 

  27. Iyer, D., L. Gambardella, W. G. Bernard, F. Serrano, V. L. Mascetti, R. A. Pedersen, A. Talasila, and S. Sinha. Robust derivation of epicardium and its differentiated smooth muscle cell progeny from human pluripotent stem cells. Development. 142(8):1528–1541, 2015

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Jiang, Y. Z., L. K. Chen, D. C. Zhu, G. R. Zhang, C. Guo, Y. Y. Qi, and H. W. Ouyang. The inductive effect of bone morphogenetic protein-4 on chondral-lineage differentiation and in situ cartilage repair. Tissue Eng. A. 16(5):1621–1632, 2010

    Article  CAS  Google Scholar 

  29. Jumabay, M., R. Abdmaulen, S. Urs, S. Heydarkhan-Hagvall, G. D. Chazenbalk, M. C. Jordan, K. P. Roos, Y. C. Yao, and K. I. Bostrom. Endothelial differentiation in multipotent cells derived from mouse and human white mature adipocytes. J. Mol. Cell. Cardiol. 53(6):790–800, 2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kang, H., B. N. Davis-Dusenbery, P. H. Nguyen, A. Lal, J. Lieberman, L. Van Aelst, G. Lagna, and A. Hata. Bone morphogenetic protein 4 promotes vascular smooth muscle contractility by activating microRNA-21 (miR-21), which down-regulates expression of family of dedicator of cytokinesis (DOCK) proteins. J. Biol. Chem. 287(6):3976–3986, 2012

    Article  CAS  PubMed  Google Scholar 

  31. Khanal, A., I. Yoshioka, K. Tominaga, N. Furuta, M. Habu, and J. Fukuda. The BMP signaling and its Smads in mandibular distraction osteogenesis. Oral Dis. 14(4):347–355, 2008

    Article  CAS  PubMed  Google Scholar 

  32. Kim, E. J., H. N. Mai, D. J. Lee, K. H. Kim, S. J. Lee, and H. S. Jung. Strategies for differentiation of hiPSCs into dental epithelial cell lineage. Cell Tissue Res. 386(2):415–421, 2021

    Article  CAS  PubMed  Google Scholar 

  33. Kim, S., A. Hata, and H. Kang. Down-regulation of miR-96 by bone morphogenetic protein signaling is critical for vascular smooth muscle cell phenotype modulation. J. Cell. Biochem. 115(5):889–895, 2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kim, S. H. L., S. S. Lee, I. Kim, J. Kwon, S. Kwon, T. Bae, J. Hur, H. J. Lee, and N. S. Hwang. Ectopic transient overexpression of OCT-4 facilitates BMP4-induced osteogenic transdifferentiation of human umbilical vein endothelial cells. J. Tissue Eng. 11:2041731420909208, 2020

    Article  PubMed  PubMed Central  Google Scholar 

  35. Krouwels, A., J. D. Iljas, A. H. M. Kragten, W. J. A. Dhert, F. C. Oner, M. A. Tryfonidou, and L. B. Creemers. Bone morphogenetic proteins for nucleus pulposus regeneration. Int. J. Mol. Sci. 21(8):2720, 2020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lee, J., S. Kang, K. C. Lilja, K. J. Colletier, C. J. F. Scheitz, Y. V. Zhang, and T. Tumbar. Signalling couples hair follicle stem cell quiescence with reduced histone H3 K4/K9/K27me3 for proper tissue homeostasis. Nat. Commun. 7:11278, 2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li, H. S., A. P. Lu, Y. Tang, S. Beckman, N. Nakayama, M. Poddar, M. V. Hogan, and J. Huard. The superior regenerative potential of muscle-derived stem cells for articular cartilage repair is attributed to high cell survival and chondrogenic potential. Mol. Ther. Methods Clin. Dev. 3:16065, 2016

    Article  PubMed  PubMed Central  Google Scholar 

  38. Li, Q., S. Q. Zhang, Y. Sui, X. M. Fu, Y. Li, and S. C. Wei. Sequential stimulation with different concentrations of BMP4 promotes the differentiation of human embryonic stem cells into dental epithelium with potential for tooth formation. Stem Cell Res. Ther. 10(1):276, 2019

    Article  PubMed  PubMed Central  Google Scholar 

  39. Li, X. Q., L. Gao, L. J. Zheng, J. Shi, and J. L. Ma. BMP4-mediated autophagy is involved in the metastasis of hepatocellular carcinoma via JNK/Beclin1 signaling. Am. J. Transl. Res. 12(6):3068–3077, 2020

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Liu, L., X. Wei, R. Huang, J. Q. Ling, L. P. Wu, and Y. Xiao. Effect of bone morphogenetic protein-4 on the expression of Sox2, Oct-4, and c-Myc in human periodontal ligament cells during long-term culture. Stem Cells Dev. 22(11):1670–1677, 2013

    Article  CAS  PubMed  Google Scholar 

  41. Liu, L., Y. F. Liu, J. Zhang, Y. Z. Duan, and Y. Jin. Ameloblasts serum-free conditioned medium: bone morphogenic protein 4-induced odontogenic differentiation of mouse induced pluripotent stem cells. J. Tissue Eng. Regen. Med. 10(6):466–474, 2016

    Article  CAS  PubMed  Google Scholar 

  42. Liu, L., Z. J. Peng, Z. Z. Xu, H. Q. Huang, and X. Wei. Mouse embryonic fibroblast (MEF)/BMP4-conditioned medium enhanced multipotency of human dental pulp cells. J. Mol. Histol. 49(1):17–26, 2018

    Article  CAS  PubMed  Google Scholar 

  43. Lu, H. X., N. Kawazoe, T. Kitajima, Y. Myoken, M. Tomita, A. Umezawa, G. P. Chen, and Y. Ito. Spatial immobilization of bone morphogenetic protein-4 in a collagen-PLGA hybrid scaffold for enhanced osteoinductivity. Biomaterials. 33(26):6140–6146, 2012

    Article  CAS  PubMed  Google Scholar 

  44. Miljkovic, N. D., G. M. Cooper, and K. G. Marra. Chondrogenesis, bone morphogenetic protein-4 and mesenchymal stem cells. Osteoarthr. Cartil. 16(10):1121–1130, 2008

    Article  CAS  Google Scholar 

  45. Ninomiya, N., T. Michiue, M. Asashima, and A. Kurisaki. BMP signaling regulates the differentiation of mouse embryonic stem cells into lung epithelial cell lineages. In Vitro Cell. Dev. Biol. Anim. 49(3):230–237, 2013

    Article  CAS  PubMed  Google Scholar 

  46. Ou, M. M., Y. B. Zhao, F. M. Zhang, and X. F. Huang. Bmp2 and Bmp4 accelerate alveolar bone development. Connect. Tissue Res. 56(3):204–211, 2015

    Article  CAS  PubMed  Google Scholar 

  47. Peng, T., G. H. Zhu, Y. P. Dong, J. J. Zeng, W. Li, W. W. Guo, Y. Chen, M. L. Duan, B. Hocher, and D. H. Xie. BMP4: a possible key factor in differentiation of auditory neuron-like cells from bone-derived mesenchymal stromal cells. Clin. Lab. 61(9):1171–1178, 2015

    CAS  PubMed  Google Scholar 

  48. Rahman, M. S., N. Akhtar, H. M. Jamil, R. S. Banik, and S. M. Asaduzzaman. TGF-β/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation. Bone Res. 3:15005, 2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Richter, A., L. Valdimarsdottir, H. E. Hrafnkelsdottir, J. F. Runarsson, A. R. Omarsdottir, D. Ward-van Oostwaard, C. Mummery, and G. Valdimarsdottir. BMP4 promotes EMT and mesodermal commitment in human embryonic stem cells via SLUG and MSX2. Stem Cells. 32(3):636–648, 2014

    Article  CAS  PubMed  Google Scholar 

  50. Romanelli, S. M., K. R. Fath, A. P. Phekoo, G. A. Knoll, and I. A. Banerjee. Layer-by-layer assembly of peptide based bioorganic-inorganic hybrid scaffolds and their interactions with osteoblastic MC3T3-E1 cells. Mater. Sci. Eng. C. 51:316–328, 2015

    Article  CAS  Google Scholar 

  51. Salazar, V. S., L. W. Gamer, and V. Rosen. BMP signaling in skeletal development, disease and repair. Nat. Rev. Endocrinol. 12(4):203–221, 2016

    Article  CAS  PubMed  Google Scholar 

  52. Seki, D., N. Takeshita, T. Oyanagi, S. Sasaki, I. Takano, M. Hasegawa, and T. Takano-Yamamoto. Differentiation of odontoblast-like cells from mouse induced pluripotent stem cells by Pax9 and Bmp4 transfection. Stem Cells Transl. Med. 4(9):993–997, 2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sepac, A., K. Si-Tayeb, F. Sedlic, S. Barrett, S. Canfield, S. A. Duncan, Z. J. Bosnjak, and J. W. Lough. Comparison of cardiomyogenic potential among human ESC and iPSC lines. Cell Transplant. 21(11):2523–2530, 2012

    Article  PubMed  Google Scholar 

  54. Shahlaie, K., and K. D. Kim. Occipitocervical fusion using recombinant human bone morphogenetic protein-2. Spine. 33(21):2361–2366, 2008

    Article  PubMed  Google Scholar 

  55. Shen, J., A. W. James, J. N. Zara, G. Asatrian, K. Khadarian, J. B. Zhang, S. Ho, H. J. Kim, K. Ting, and C. Soo. BMP2-induced inflammation can be suppressed by the osteoinductive growth factor NELL-1. Tissue Eng. A. 19(21–22):2390–2401, 2013

    Article  CAS  Google Scholar 

  56. Shen, S. T., S. R. Wang, Y. X. He, H. C. Hu, B. Y. Yao, and Y. Zhang. Regulation of bone morphogenetic protein 4 on epithelial tissue. J. Cell Commun. Signal. 14(3):283–292, 2020

    Article  PubMed  PubMed Central  Google Scholar 

  57. Shi, J. J., X. Zhang, J. X. Zhu, Y. B. Pi, X. Q. Hu, C. Y. Zhou, and Y. F. Ao. Nanoparticle delivery of the Bone Morphogenetic Protein 4 gene to adipose-derived stem cells promotes articular cartilage repair in vitro and in vivo. Arthroscopy. 29(12):2001–2011, 2013

    Article  PubMed  Google Scholar 

  58. Shiozaki, Y., T. Kitajima, T. Mazaki, A. Yoshida, M. Tanaka, A. Umezawa, M. Nakamura, Y. Yoshida, Y. Ito, T. Ozaki, and A. Matsukawa. Enhanced in vivo osteogenesis by nanocarrier-fused bone morphogenetic protein-4. Int. J. Nanomed. 8:1349–1360, 2013

    Google Scholar 

  59. Srisuwan, T., D. J. Tilkorn, S. Al-Benna, A. Vashi, A. Penington, H. H. Messer, K. M. Abbertone, and E. W. Thompson. Survival of rat functional dental pulp cells in vascularized tissue engineering chambers. Tissue Cell. 44(2):111–121, 2012

    Article  CAS  PubMed  Google Scholar 

  60. Swartz, E. W., J. Baek, M. Pribadi, K. J. Wojta, S. Almeida, A. Karydas, F. B. Gao, B. L. Miller, and G. Coppola. A novel protocol for directed differentiation of C9orf72-associated human induced pluripotent stem cells into contractile skeletal myotubes. Stem Cells Transl. Med. 5(11):1461–1472, 2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Takasato, M., P. X. Er, M. Becroft, J. M. Vanslambrouck, E. G. Stanley, A. G. Elefanty, and M. H. Little. Directing human embryonic stem cell differentiation towards a renal lineage generates a self-organizing kidney. Nat. Cell Biol. 16(1):118–126, 2014

    Article  CAS  PubMed  Google Scholar 

  62. Tan, Q., Y. Y. Cao, X. R. Zheng, M. T. Peng, E. Y. Huang, and J. H. Wang. BMP4-regulated human dental pulp stromal cells promote pulp-like tissue regeneration in a decellularized dental pulp matrix scaffold. Odontology. 109(4):895–903, 2021

    Article  CAS  PubMed  Google Scholar 

  63. Tang, Y., S. W. Qian, M. Y. Wu, J. Wang, P. Lu, X. Li, H. Y. Huang, L. Guo, X. Sun, C. J. Xu, and Q. Q. Tang. BMP4 mediates the interplay between adipogenesis and angiogenesis during expansion of subcutaneous white adipose tissue. J. Mol. Cell. Biol. 8(4):302–312, 2016

    Article  CAS  PubMed  Google Scholar 

  64. Tarantino, U., M. Scimeca, E. Piccirilli, V. Tancredi, J. Baldi, E. Gasbarra, and E. Bonanno. Sarcopenia: a histological and immunohistochemical study on age-related muscle impairment. Aging Clin. Exp. Res. 27:S51–S60, 2015

    Article  PubMed  Google Scholar 

  65. Thompson, A., M. Berry, A. Logan, and Z. Ahmed. Activation of the BMP4/Smad1 pathway promotes retinal ganglion cell survival and axon regeneration. Investig. Ophthalmol. Vis. Sci. 60(5):1748–1759, 2019

    Article  CAS  Google Scholar 

  66. Tian, K., M. Qi, L. M. Wang, Z. F. Li, J. Z. Xu, Y. Li, G. L. Liu, B. Wang, J. Huard, and G. H. Li. Two-stage therapeutic utility of ectopically formed bone tissue in skeletal muscle induced by adeno-associated virus containing bone morphogenetic protein-4 gene. J. Orthop. Surg. Res. 10:86, 2015

    Article  PubMed  PubMed Central  Google Scholar 

  67. Umebayashi, M., Y. Sumita, Y. Kawai, S. Watanabe, and I. Asahina. Gene-activated matrix comprised of atelocollagen and plasmid DNA encoding BMP4 or Runx2 promotes rat cranial bone augmentation. BioRes. Open Access. 4(1):164–174, 2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Vukicevic, S., H. Oppermann, D. Verbanac, M. Jankolija, I. Popek, J. Curak, J. Brkljacic, M. Pauk, I. Erjavec, I. Francetic, I. Dumic-Cule, M. Jelic, D. Durdevic, T. Vlahovic, R. Novak, V. Kufner, T. B. Niksic, M. Kozlovic, Z. B. Tomisic, J. Bubic-Spoljar, I. Bastalic, S. Vikic-Topic, M. Peric, M. Pecina, and L. Grgurevic. The clinical use of bone morphogenetic proteins revisited: a novel biocompatible carrier device OSTEOGROW for bone healing. Int. Orthop. 38(3):635–647, 2014

    Article  PubMed  Google Scholar 

  69. Wagner, I., H. Wang, P. M. Weissert, W. L. Straube, A. Shevchenko, M. Gentzel, G. Brito, A. Tazaki, C. Oliveira, T. Sugiura, A. Shevchenko, A. Simon, D. N. Drechsel, and E. M. Tanaka. Serum proteases potentiate BMP-induced cell cycle re-entry of dedifferentiating muscle cells during newt limb regeneration. Dev. Cell. 40(6):608–617, 2017

    Article  CAS  PubMed  Google Scholar 

  70. Wang, J., S. B. Greene, M. Bonilla-Claudio, Y. Tao, J. Zhang, Y. Bai, Z. Huang, B. L. Black, F. Wang, and J. F. Martin. Bmp signaling regulates myocardial differentiation from cardiac progenitors through a MicroRNA-mediated mechanism. Dev. Cell. 19(6):903–912, 2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wang, R. N., J. Green, Z. Wang, Y. Deng, M. Qiao, M. Peabody, Q. Zhang, J. Ye, Z. Yan, S. Denduluri, O. Idowu, M. Li, C. Shen, A. Hu, R. C. Haydon, R. Kang, J. Mok, M. J. Lee, H. L. Luu, and L. L. Shi. Bone morphogenetic protein (BMP) signaling in development and human diseases. Genes Dis. 1(1):87–105, 2014

    Article  PubMed  PubMed Central  Google Scholar 

  72. Wang, X. X., X. S. Wang, J. J. Liu, T. Cai, L. Guo, S. J. Wang, J. M. Wang, Y. P. Cao, J. F. Ge, Y. Y. Jiang, E. E. Tredget, M. J. Cao, and Y. J. Wu. Hair follicle and sebaceous gland de novo regeneration with cultured epidermal stem cells and skin-derived precursors. Stem Cells Transl. Med. 5(12):1695–1706, 2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wertheimer, T., E. Velardi, J. Tsai, K. Cooper, S. Y. Xiao, C. C. Kloss, K. J. Ottmuller, Z. Mokhtari, C. Brede, P. deRoos, S. Kinsella, B. Palikuqi, M. Ginsberg, L. F. Young, F. Kreines, S. R. Lieberman, A. Lazrak, P. P. Guo, F. Malard, O. M. Smith, Y. Shono, R. R. Jenq, A. M. Hanash, D. J. Nolan, J. M. Butler, A. Beilhack, N. R. Manley, S. Rafe, J. A. Dudakov, and M. R. M. Van den Brink. Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration. Sci. Immunol. 3(19):eaal2736, 2018

    Article  PubMed  PubMed Central  Google Scholar 

  74. Wozney, J. M., V. Rosen, A. J. Celeste, L. M. Mitsock, M. J. Whitters, R. W. Kriz, R. M. Hewick, and E. A. Wang. Novel regulators of bone formation: molecular clones and activities. Science. 242(4885):1528–1534, 1988

    Article  CAS  PubMed  Google Scholar 

  75. Yamazaki, A., M. Yashiro, S. Mii, R. Aki, Y. Hamada, N. Arakawa, K. Kawahara, R. M. Hoffman, and Y. Amoh. Isoproterenol directs hair follicle-associated pluripotent (HAP) stem cells to differentiate in vitro to cardiac muscle cells which can be induced to form beating heart-muscle tissue sheets. Cell Cycle. 15(5):760–765, 2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Yang, D. D., S. B. Chen, C. Z. Gao, X. B. Liu, Y. L. Zhou, P. F. Liu, and J. L. Cai. Chemically defined serum-free conditions for cartilage regeneration from human embryonic stem cells. Life Sci. 164:9–14, 2016

    Article  CAS  PubMed  Google Scholar 

  77. Yogi, A., M. Rukhlova, C. Charlebois, G. H. Tian, D. B. Stanimirovic, and M. J. Moreno. Differentiation of adipose-derived stem cells into vascular smooth muscle cells for tissue engineering applications. Biomedicines. 9(7):797, 2021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zhang, J. H., M. Klos, G. F. Wilson, A. M. Herman, X. J. Lian, K. K. Raval, M. R. Barron, L. Q. Hou, A. G. Soerens, J. Y. Yu, S. P. Palecek, G. E. Lyons, J. A. Thomson, T. J. Herron, J. Jalife, and T. J. Kamp. Extracellular matrix promotes highly efficient cardiac differentiation of human pluripotent stem cells the matrix sandwich method. Circ. Res. 111(9):1125–1136, 2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhang, Y. C., Y. L. Li, R. R. Shi, S. Q. Zhang, H. Liu, Y. F. Zheng, Y. Li, J. L. Cai, D. Q. Pei, and S. C. Wei. Generation of tooth–periodontium complex structures using high-odontogenic potential dental epithelium derived from mouse embryonic stem cells. Stem Cell. Res. Ther. 8:141, 2017

    Article  PubMed  PubMed Central  Google Scholar 

  80. Zheng, L. W., L. Linthicum, P. K. DenBesten, and Y. Zhang. The similarity between human embryonic stem cell-derived epithelial cells and ameloblast-lineage cells. Int. J. Oral Sci. 5(1):1–6, 2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by Zhejiang Provincial Key Research and Development Program of China (No. 2021C03113). We thank American Journal Experts for its linguistic assistance of this manuscript.

Author information

Author notes

  1. Yiqi Pan and Zhiwei Jiang have contributed equally to this study.

Authors and Affiliations

  1. Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, 310006, China

    Yiqi Pan, Zhiwei Jiang, Yuer Ye, Danji Zhu, Na Li, Guoli Yang & Ying Wang

Authors
  1. Yiqi Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhiwei Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuer Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Danji Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Na Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guoli Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ying Wang.

Additional information

Associate Editor Emmanuel Opara oversaw the review of this article.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pan, Y., Jiang, Z., Ye, Y. et al. Role and Mechanism of BMP4 in Regenerative Medicine and Tissue Engineering. Ann Biomed Eng 51, 1374–1389 (2023). https://doi.org/10.1007/s10439-023-03173-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10439-023-03173-6

Keywords

Search

Navigation