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Development of Human Brain Organoids, The Formation of Neural Circuits and Relationship with Neurodevelopmental Diseases

Yıl 2025, Cilt: 18 Sayı: 1, 30 - 36, 31.07.2025
https://doi.org/10.58688/kujs.1534932

Öz

İnsan kaynaklı pluripotent kök hücreleri (hiPSC'ler) ve insan embriyonik kök hücreleri (hESC'ler), kültür ortamında kendilerini sonsuza kadar yenileyebilen ve hemen her tür insan hücresine dönüşme potansiyeline sahip iki tür insan pluripotent kök hücre olarak bilinmektedir. Beyin organoidleri, pluripotent kök hücrelerden gelen, bilim dünyası için son derece değerli bir kaynak oluşturmaktadır. İnsan beyinlerinin patofizyolojisini, doku mühendisliğini ve gelişim süreçlerini araştırmak için kullanılmakta olup, doğal büyüme mekanizmaları taklit edebilme özellikleriyle dikkat çekerler. Özellikle, insan embriyonik kök hücrelerinden elde edilen insan kortikal organoidleri (hCO'lar), insan beyninin gelişimi ve bozukluklarını 3B dokuda ayrıntılı incelemek için mükemmel bir model sunmaktadır. Ancak, bu alandaki ilerlemelere rağmen, hala bir dizi cevapsız soru vardır. Bunlar arasında işlevsiz kan atardamarları, mikroglianın yetersiz gelişimi ve korteksin altı farklı katmanının tam anlamıyla oluşturulamaması bu modellerin sınırlılıkları arasında yer almaktadır. Bununla birlikte, modern hCO'larda mikro damarlanmanın olmaması, hCO'ların iç bölgelerine ulaşabilen oksijen ve besin miktarını sınırlamaktadır. Bu inceleme kapsamında, beyin organoidlerinin oluşturulma yöntemleri, bu süreçte yaşanan zorluklar ele alınmaktadır. Ayrıca, beyin organoidlerinin geliştirilmesi ve ilgili son yenilikler ve bu teknolojinin erken beyin gelişimi ile nörolojik bozuklukların araştırılmasındaki potansiyel kullanımları üzerine güncel bilgiler sunulmaktadır.

Kaynakça

  • Avior Y., Sagi I., Benvenisty N. (2016). Pluripotent stem cells in disease modelling and drug discovery. Nat Rev Mol Cell Biol, 17(3), 170-182.
  • Azevedo F.A., Carvalho L.R., Grinberg L.T., Farfel J.M., Ferretti R.E., Leite R.E., Herculano-Houzel S. (2009). Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J Comp Neurol, 513(5), 532-541.
  • Birey F., Andersen J., Makinson C.D., Islam S., Wei W., Huber N., Paşca S.P. (2017). Assembly of functionally integrated human forebrain spheroids. Nature, 545(7652), 54-59.
  • Biswas A., Hutchins R. (2007). Embryonic stem cells. Stem Cells Dev, 16(2), 213-222.
  • Bongso A., Fong C.Y., Ng S.C., Ratnam S. (1994). Isolation and culture of inner cell mass cells from human blastocysts. Hum Reprod, 9(11), 2110-2117.
  • Cakir B., Xiang Y., Tanaka Y., Kural M.H., Parent M., Kang Y.J., Park I.H. (2019). Engineering of human brain organoids with a functional vascular-like system. Nat Methods, 16(11), 1169-1175.
  • Camp J.G., Badsha F., Florio M., Kanton S., Gerber T., Wilsch-Bräuninger M., Treutlein B. (2015). Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc Natl Acad Sci U S A, 112(51), 15672-15677.
  • Clowry G.J., Alzu'bi A., Harkin L.F., Sarma S., Kerwin J., Lindsay S.J. (2018). Charting the protomap of the human telencephalon. Semin Cell Dev Biol, 76, 3-14.
  • Contessi Negrini N., Angelova Volponi A., Higgins C.A., Sharpe P.T., Celiz A.D. (2021). Scaffold-based developmental tissue engineering strategies for ectodermal organ regeneration. Materials today. Bio, 10, 100107.
  • Dai Z., Lin Q., Li T., Wang X., Yuan H., Yu X., Wang H. (2019). Disrupted structural and functional brain networks in Alzheimer's disease. Neurobiol Aging, 75, 71-82.
  • Geschwind D.H., Rakic P. (2013). Cortical evolution: judge the brain by its cover. Neuron, 80(3), 633-647.
  • Heide M., Huttner W.B., Mora-Bermúdez F. (2018). Brain organoids as models to study human neocortex development and evolution. Curr Opin Cell Biol, 55, 8-16.
  • Jo J., Xiao Y., Sun A.X., Cukuroglu E., Tran H.D., Göke J., Ng H.H. (2016). Midbrain-like Organoids from Human Pluripotent Stem Cells Contain Functional Dopaminergic and Neuromelanin-Producing Neurons. Cell Stem Cell, 19(2), 248-257.
  • Jorfi M., D'Avanzo C., Kim D.Y., Irimia D. (2018). Three-Dimensional Models of the Human Brain Development and Diseases. Adv Healthc Mater, 7(1).
  • Kadoshima T., Sakaguchi H., Nakano T., Soen M., Ando S., Eiraku M., Sasai Y. (2013). Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex. Proc Natl Acad Sci U S A, 110(50), 20284-20289.
  • Klaus J., Kanton S., Kyrousi C., Ayo-Martin A.C., Di Giaimo R., Riesenberg S., Cappello S. (2019). Altered neuronal migratory trajectories in human cerebral organoids derived from individuals with neuronal heterotopia. Nat Med, 25(4), 561-568.
  • Lancaster M.A., Corsini N.S., Wolfinger S., Gustafson E.H., Phillips A.W., Burkard T.R., Knoblich J.A. (2017). Guided self-organization and cortical plate formation in human brain organoids. Nat Biotechnol, 35(7), 659-666.
  • Lancaster M.A., Knoblich J.A. (2014). Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc, 9(10), 2329-2340.
  • Lancaster M.A., Renner M., Martin C.A., Wenzel D., Bicknell L.S., Hurles M.E., Knoblich J.A. (2013). Cerebral organoids model human brain development and microcephaly. Nature, 501(7467), 373-379.
  • Leung C., Jia, Z. (2016). Mouse Genetic Models of Human Brain Disorders. Front Genet, 7, 40.
  • Liu G., David B., Trawczynski M., Fessler R.G. (2019). Advances in Pluripotent Stem Cells: History, Mechanisms, Technologies, and Applications. Stem Cell Rev Rep. Nov 23;16(1):3–32.
  • Mariani J., Coppola G., Zhang P., Abyzov A., Provini L., Tomasini L., Vaccarino F.M. (2015). FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders. Cell, 162(2), 375-390.
  • Martin G. R. (1981). Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci U S A, 78(12), 7634-7638.
  • Molnár Z., Clowry G.J., Šestan N., Alzu'bi A., Bakken T., Hevner R.F., Kriegstein A. (2019). New insights into the development of the human cerebral cortex. J Anat, 235(3), 432-451.
  • Moore K., Persaud V., Shiota K. (2000). Color atlas of clinical embryology / Keith L. Moore, T. V. N. Persaud, Kohei Shiota.
  • Ohnuki M., Takahashi K. (2015). Present and future challenges of induced pluripotent stem cells. Philos Trans R Soc Lond B Biol Sci, 370(1680), 20140367.
  • Pașca S.P. (2018). The rise of three-dimensional human brain cultures. Nature, 553(7689), 437-445.
  • Paşca A.M., Sloan S.A., Clarke L.E., Tian Y., Makinson C.D., Huber N., Paşca S.P. (2015). Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods, 12(7), 671-678.
  • Qian X., Nguyen H.N., Song M.M., Hadiono C., Ogden S.C., Hammack C., Ming G.L. (2016). Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure. Cell, 165(5), 1238-1254.
  • Qian X., Song H., Ming G.L. (2019). Brain organoids: advances, applications and challenges. Development, 146(8).
  • Renner M., Lancaster M.A., Bian S., Choi H., Ku T., Peer A., Knoblich J.A. (2017). Self-organized developmental patterning and differentiation in cerebral organoids. Embo j, 36(10), 1316-1329.
  • Seto Y., Eiraku M. (2019). Toward the formation of neural circuits in human brain organoids. Curr Opin Cell Biol, 61, 86-91.
  • Shen Q., Goderie S.K., Jin L., Karanth N., Sun Y., Abramova N., Temple S. (2004). Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science, 304(5675), 1338-1340.
  • Takahashi K., Yamanaka S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663-676.
  • Thoma C.R., Zimmermann M., Agarkova I., Kelm J.M., Krek W. (2014). 3D cell culture systems modeling tumor growth determinants in cancer target discovery. Adv Drug Deliv Rev, 69-70, 29-41.
  • Thomson J.A., Itskovitz-Eldor J., Shapiro S.S., Waknitz M.A., Swiergiel J.J., Marshall V.S., Jones J.M. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282(5391), 1145-1147.
  • Trujillo C.A., Muotri A.R. (2018). Brain Organoids and the Study of Neurodevelopment. Trends Mol Med, 24(12), 982-990.
  • Zhao X., Bhattacharyya A. (2018). Human Models Are Needed for Studying Human Neurodevelopmental Disorders. Am J Hum Genet, 103(6), 829-857.
  • Zhu W., Ma X., Gou M., Mei D., Zhang K., Chen S. (2016). 3D printing of functional biomaterials for tissue engineering. Current Opinion in Biotechnology, 40, 103-112.

Development of Human Brain Organoids, The Formation of Neural Circuits and Relationship with Neurodevelopmental Diseases

Yıl 2025, Cilt: 18 Sayı: 1, 30 - 36, 31.07.2025
https://doi.org/10.58688/kujs.1534932

Öz

Human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) are known as two types of human pluripotent stem cells (hPSCs) capable of self-renewing indefinitely in culture and differentiating into almost any type of human cell. Brain organoids, derived from pluripotent stem cells, serve as an extremely valuable resource for the scientific community. They are utilized to study the pathophysiology, tissue engineering, and development processes of human brains, distinguished by their ability to mimic natural growth mechanisms. In particular, human cortical organoids (hCOs) derived from human embryonic stem cells provide an excellent model for detailed three-dimensional investigations of human brain development and disorders. Despite advancements in this field, several unresolved issues persist. These limitations include non-functional blood arteries, restricted development of microglia, and the incomplete formation of the six distinct layers of the cortex. Additionally, the lack of microvascularization in modern hCOs limits the amount of oxygen and nutrients that can reach the inner regions of the hCOs. This review addresses the methods used for creating brain organoids and examines the challenges encountered in these processes. Furthermore, it highlights the latest advancements in the development of brain organoids and provides updated insights into their potential applications in studying early brain development and neurological disorders.

Kaynakça

  • Avior Y., Sagi I., Benvenisty N. (2016). Pluripotent stem cells in disease modelling and drug discovery. Nat Rev Mol Cell Biol, 17(3), 170-182.
  • Azevedo F.A., Carvalho L.R., Grinberg L.T., Farfel J.M., Ferretti R.E., Leite R.E., Herculano-Houzel S. (2009). Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J Comp Neurol, 513(5), 532-541.
  • Birey F., Andersen J., Makinson C.D., Islam S., Wei W., Huber N., Paşca S.P. (2017). Assembly of functionally integrated human forebrain spheroids. Nature, 545(7652), 54-59.
  • Biswas A., Hutchins R. (2007). Embryonic stem cells. Stem Cells Dev, 16(2), 213-222.
  • Bongso A., Fong C.Y., Ng S.C., Ratnam S. (1994). Isolation and culture of inner cell mass cells from human blastocysts. Hum Reprod, 9(11), 2110-2117.
  • Cakir B., Xiang Y., Tanaka Y., Kural M.H., Parent M., Kang Y.J., Park I.H. (2019). Engineering of human brain organoids with a functional vascular-like system. Nat Methods, 16(11), 1169-1175.
  • Camp J.G., Badsha F., Florio M., Kanton S., Gerber T., Wilsch-Bräuninger M., Treutlein B. (2015). Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc Natl Acad Sci U S A, 112(51), 15672-15677.
  • Clowry G.J., Alzu'bi A., Harkin L.F., Sarma S., Kerwin J., Lindsay S.J. (2018). Charting the protomap of the human telencephalon. Semin Cell Dev Biol, 76, 3-14.
  • Contessi Negrini N., Angelova Volponi A., Higgins C.A., Sharpe P.T., Celiz A.D. (2021). Scaffold-based developmental tissue engineering strategies for ectodermal organ regeneration. Materials today. Bio, 10, 100107.
  • Dai Z., Lin Q., Li T., Wang X., Yuan H., Yu X., Wang H. (2019). Disrupted structural and functional brain networks in Alzheimer's disease. Neurobiol Aging, 75, 71-82.
  • Geschwind D.H., Rakic P. (2013). Cortical evolution: judge the brain by its cover. Neuron, 80(3), 633-647.
  • Heide M., Huttner W.B., Mora-Bermúdez F. (2018). Brain organoids as models to study human neocortex development and evolution. Curr Opin Cell Biol, 55, 8-16.
  • Jo J., Xiao Y., Sun A.X., Cukuroglu E., Tran H.D., Göke J., Ng H.H. (2016). Midbrain-like Organoids from Human Pluripotent Stem Cells Contain Functional Dopaminergic and Neuromelanin-Producing Neurons. Cell Stem Cell, 19(2), 248-257.
  • Jorfi M., D'Avanzo C., Kim D.Y., Irimia D. (2018). Three-Dimensional Models of the Human Brain Development and Diseases. Adv Healthc Mater, 7(1).
  • Kadoshima T., Sakaguchi H., Nakano T., Soen M., Ando S., Eiraku M., Sasai Y. (2013). Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex. Proc Natl Acad Sci U S A, 110(50), 20284-20289.
  • Klaus J., Kanton S., Kyrousi C., Ayo-Martin A.C., Di Giaimo R., Riesenberg S., Cappello S. (2019). Altered neuronal migratory trajectories in human cerebral organoids derived from individuals with neuronal heterotopia. Nat Med, 25(4), 561-568.
  • Lancaster M.A., Corsini N.S., Wolfinger S., Gustafson E.H., Phillips A.W., Burkard T.R., Knoblich J.A. (2017). Guided self-organization and cortical plate formation in human brain organoids. Nat Biotechnol, 35(7), 659-666.
  • Lancaster M.A., Knoblich J.A. (2014). Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc, 9(10), 2329-2340.
  • Lancaster M.A., Renner M., Martin C.A., Wenzel D., Bicknell L.S., Hurles M.E., Knoblich J.A. (2013). Cerebral organoids model human brain development and microcephaly. Nature, 501(7467), 373-379.
  • Leung C., Jia, Z. (2016). Mouse Genetic Models of Human Brain Disorders. Front Genet, 7, 40.
  • Liu G., David B., Trawczynski M., Fessler R.G. (2019). Advances in Pluripotent Stem Cells: History, Mechanisms, Technologies, and Applications. Stem Cell Rev Rep. Nov 23;16(1):3–32.
  • Mariani J., Coppola G., Zhang P., Abyzov A., Provini L., Tomasini L., Vaccarino F.M. (2015). FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders. Cell, 162(2), 375-390.
  • Martin G. R. (1981). Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci U S A, 78(12), 7634-7638.
  • Molnár Z., Clowry G.J., Šestan N., Alzu'bi A., Bakken T., Hevner R.F., Kriegstein A. (2019). New insights into the development of the human cerebral cortex. J Anat, 235(3), 432-451.
  • Moore K., Persaud V., Shiota K. (2000). Color atlas of clinical embryology / Keith L. Moore, T. V. N. Persaud, Kohei Shiota.
  • Ohnuki M., Takahashi K. (2015). Present and future challenges of induced pluripotent stem cells. Philos Trans R Soc Lond B Biol Sci, 370(1680), 20140367.
  • Pașca S.P. (2018). The rise of three-dimensional human brain cultures. Nature, 553(7689), 437-445.
  • Paşca A.M., Sloan S.A., Clarke L.E., Tian Y., Makinson C.D., Huber N., Paşca S.P. (2015). Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods, 12(7), 671-678.
  • Qian X., Nguyen H.N., Song M.M., Hadiono C., Ogden S.C., Hammack C., Ming G.L. (2016). Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure. Cell, 165(5), 1238-1254.
  • Qian X., Song H., Ming G.L. (2019). Brain organoids: advances, applications and challenges. Development, 146(8).
  • Renner M., Lancaster M.A., Bian S., Choi H., Ku T., Peer A., Knoblich J.A. (2017). Self-organized developmental patterning and differentiation in cerebral organoids. Embo j, 36(10), 1316-1329.
  • Seto Y., Eiraku M. (2019). Toward the formation of neural circuits in human brain organoids. Curr Opin Cell Biol, 61, 86-91.
  • Shen Q., Goderie S.K., Jin L., Karanth N., Sun Y., Abramova N., Temple S. (2004). Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science, 304(5675), 1338-1340.
  • Takahashi K., Yamanaka S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663-676.
  • Thoma C.R., Zimmermann M., Agarkova I., Kelm J.M., Krek W. (2014). 3D cell culture systems modeling tumor growth determinants in cancer target discovery. Adv Drug Deliv Rev, 69-70, 29-41.
  • Thomson J.A., Itskovitz-Eldor J., Shapiro S.S., Waknitz M.A., Swiergiel J.J., Marshall V.S., Jones J.M. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282(5391), 1145-1147.
  • Trujillo C.A., Muotri A.R. (2018). Brain Organoids and the Study of Neurodevelopment. Trends Mol Med, 24(12), 982-990.
  • Zhao X., Bhattacharyya A. (2018). Human Models Are Needed for Studying Human Neurodevelopmental Disorders. Am J Hum Genet, 103(6), 829-857.
  • Zhu W., Ma X., Gou M., Mei D., Zhang K., Chen S. (2016). 3D printing of functional biomaterials for tissue engineering. Current Opinion in Biotechnology, 40, 103-112.
Toplam 39 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Hücre Gelişimi, Proliferasyon ve Ölümü, Biyokimya ve Hücre Biyolojisi (Diğer), Genetik (Diğer), Tıbbi Biyoteknoloji (Diğer), Biyomühendislik (Diğer)
Bölüm Makaleler
Yazarlar

Yağmur Kırbayır 0009-0007-0240-7284

Hatice Bashir 0009-0007-3495-4629

Sude Naz Çataltepe 0009-0009-0441-5696

Nigar Sahra Karabul 0009-0009-5188-3986

Pelin Saraçoğlu 0000-0002-9701-4286

Murat Ihlamur 0000-0002-0458-5638

Yayımlanma Tarihi 31 Temmuz 2025
Gönderilme Tarihi 19 Ağustos 2024
Kabul Tarihi 15 Temmuz 2025
Yayımlandığı Sayı Yıl 2025 Cilt: 18 Sayı: 1

Kaynak Göster

APA Kırbayır, Y., Bashir, H., Çataltepe, S. N., … Karabul, N. S. (2025). Development of Human Brain Organoids, The Formation of Neural Circuits and Relationship with Neurodevelopmental Diseases. Kafkas Üniversitesi Fen Bilimleri Enstitüsü Dergisi, 18(1), 30-36. https://doi.org/10.58688/kujs.1534932