Kontakt

Dr. Maryam Hatami

Group Leader


Anatomie und Zellbiologie
Im Neuenheimer Feld 307
69120 Heidelberg
Tel. 06221-54-8343
Email


Hatami

Treatment options for Alzheimer’s disease

We are employing neuronal, embryonic and induced pluripotent stem (iPS) cells for studying the molecular mechanisms of brain development and pathology for devising novel stem cell-derived therapies.

The hippocampus and its dentate gyrus is the main relay station in the brain responsible for learning and memory as well as spatial navigation.  During the development of Alzheimer’s disease, shrinkage is especially severe in the hippocampus. We could envision specific transplantation of hippocampal neurons as a therapeutic option. 

Our research team has been pioneering the understanding of hippocampal dentate gyrus neuronal development and neuronal networking. (Front Cell Neurosci. 2018; Mol Cell Neurosci. 2010; J Biol Chem. 2010; Dev Neurosci. 2007; J Neurosci. 2004; Nat Cell Biol. 2004; Trends Neurosci. 2001)

We are analyzing the differentiation of pluripotent stem cells into hippocampal stem and progenitor cell types, which could provide the most important cell type for the regeneration of dementia such as Alzheimer’s disease.

Recently, 3D culture models termed, “cerebral organoids”, have been developed which recapitulate aspects of brain development, including the organization of discrete cortical regions. These organoids also include organized germinal zones, and both radial and tangential migration of cortical neuron subpopulations and cortical organizers. They are not patterned by externally added growth factors or morphogens, suggesting that their development relies purely on self-organization by building neuronal microenvironments. Although the development of dorsal forebrain structures such as the hippocampus is still limited in these organoids, they build a foundation for designing the histological architecture of the hippocampus and the dentate gyrus. Patient specific hippocampal organoids could be used as test platforms to screen pharmacological libraries for therapeutic applications.

During development, neuronal stem cells make fate decisions and differentiate into various mature cell types within a complex brain structure. During regeneration, differentiated cells might acquire a stem cell state and re-differentiate along multiple lineages. Single-cell genomics including PCR and sequencing provides a set of powerful methods to illuminate the intermediate states that cells go through during these transitions of cellular identities.

We could identify that the combination of central dentate gyrus transcription factors contros denate gyrus granule neuron differentiation in vitro. Furthermore, it became obvious that the combination of a dentate gyrus specific growth factor cocktail and transcription factors will lead to a significant differentiation of dentate gyrus granule neurons. These neurons could now be generated from pluripotent stem cells from healthy patients with neurodegenerative diseases and be screened for therapeutic strategies.

It is very difficult to conduct stem cell research in the frame of governmental grant applications. To establish and direct this kind of research to the clinic, we are currently looking for industrial corporations and private sponsors.  Could you imagine becoming a sponsor for our project and thus enhance medical options for patients suffering from neuro-generative diseases?

 

References:

1: Hatami M, Conrad S, Naghsh P, Alvarez-Bolado G, Skutella T. Cell-Biological

Requirements for the Generation of Dentate Gyrus Granule Neurons. Front Cell

Neurosci. 2018 Nov 12;12:402. doi: 10.3389/fncel.2018.00402. eCollection 2018.

Review. PubMed PMID: 30483057; PubMed Central PMCID: PMC6240695.

Supporting literature: 

 

 

2: Conrad S, Stimpfle F, Montazeri S, Oldekamp J, Seid K, Alvarez-Bolado G,

Skutella T. RGMb controls aggregation and migration of Neogenin-positive cells in

vitro and in vivo. Mol Cell Neurosci. 2010 Feb;43(2):222-31. doi:

10.1016/j.mcn.2009.11.003. Epub 2009 Nov 26. PubMed PMID: 19944164.

 

3: Friedrichs M, Larralde O, Skutella T, Theil T. Lamination of the cerebral

cortex is disturbed in Gli3 mutant mice. Dev Biol. 2008 Jun 1;318(1):203-14. doi:

10.1016/j.ydbio.2008.03.032. Epub 2008 Mar 28. PubMed PMID: 18448089.

 

4: Conrad S, Genth H, Hofmann F, Just I, Skutella T. Neogenin-RGMa signaling at

the growth cone is bone morphogenetic protein-independent and involves RhoA,

ROCK, and PKC. J Biol Chem. 2007 Jun 1;282(22):16423-33. Epub 2007 Mar 27.

Erratum in: J Biol Chem. 2010 Dec 31;285(53):42140. PubMed PMID: 17389603.

 

5: Skutella T, Conrad S, Hooge J, Bonin M, Alvarez-Bolado G. Microarray analysis

of the fetal hippocampus in the Emx2 mutant. Dev Neurosci. 2007;29(1-2):28-47.

PubMed PMID: 17148947.

 

6: Rajagopalan S, Deitinghoff L, Davis D, Conrad S, Skutella T, Chedotal A,

Mueller BK, Strittmatter SM. Neogenin mediates the action of repulsive guidance

molecule. Nat Cell Biol. 2004 Aug;6(8):756-62. Epub 2004 Jul 18. PubMed PMID:

15258590.

 

7: Brinks H, Conrad S, Vogt J, Oldekamp J, Sierra A, Deitinghoff L, Bechmann I,

Alvarez-Bolado G, Heimrich B, Monnier PP, Mueller BK, Skutella T. The repulsive

guidance molecule RGMa is involved in the formation of afferent connections in

the dentate gyrus. J Neurosci. 2004 Apr 14;24(15):3862-9. PubMed PMID: 15084667.

 

 8: Skutella T, Nitsch R. New molecules for hippocampal development. Trends

Neurosci. 2001 Feb;24(2):107-13. Review. PubMed PMID: 11164941.

 

 

Group Members

Richard Hertel
Heike Dietrich

 

 

 

 

 

 

 

 

 

 

 

 

Verantwortlich: E-Mail,   Letzte Änderung: Mon, 29.06.2020
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