Pantazis CB, Yang A, Lara E, McDonough JA, Blauwendraat C, Peng L, Oguro H, Kanaujiya J, Zou J, Sebesta D, Pratt G, Cross E, Blockwick J, Buxton P, Kinner-Bibeau L, Medura C, Tompkins C, Hughes S, Santiana M, Faghri F, Nalls MA, Vitale D, Ballard S, Qi YA, Ramos DM, Anderson KM, Stadler J, Narayan P, Papademetriou J, Reilly L, Nelson MP, Aggarwal S, Rosen LU, Kirwan P, Pisupati V, Coon SL, Scholz SW, Priebe T, Öttl M, Dong J, Meijer M, Janssen LJ, Lourenco VS, van der Kant R, Crusius D, Paquet D, Raulin AC, Bu G, Held A, Wainger BJ, Gabriele RM, Casey JM, Wray S, Abu-Bonsrah D, Parish CL, Beccari MS, Cleveland DW, Li E, Rose IV, Kampmann M, Calatayud Aristoy C, Verstreken P, Heinrich L, Chen MY, Schüle B, Dou D, Holzbaur EL, Zanellati MC, Basundra R, Deshmukh M, Cohen S, Khanna R, Raman M, Nevin ZS, Matia M, Van Lent J, Timmerman V, Conklin BR, Johnson Chase K, Zhang K, Funes S, Bosco DA, Erlebach L, Welzer M, Kronenberg-Versteeg D, Lyu G, Arenas E, Coccia E, Sarrafha L, Ahfeldt T, Marioni JC, Skarnes WC, Cookson MR, Ward ME, Merkle FT. A reference human induced pluripotent stem cell line for large-scale collaborative studies. Cell Stem Cell. 2022 Dec 1;29(12):1685-1702.e22. PubMed. bioRxiv

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  1. We sincerely applaud this tour de force performed in the bioRXiv preprint by Pantazis, Yang, Lara, McDonough, Blauwendraat, and Peng et al., who have taken on the tremendous effort of deeply characterizing eight well-established iPSC lines for the identification of a single reference line that could be used across the dementia research community. Although the need for such a Rosetta line, akin to the selected subset of mouse strains being used in CNS research, has been called for in the past (Volpato and Webber, 2020), it is great to see that the first explicit selection of a single reference iPSC line has now been put forward and has been made easily accessible. It will be up to the dementia community to scrutinize the utility of this line over the years to come, but we foresee that the inclusion of such a Rosetta line across iPSC experiments could substantially aid in the inter- and cross-laboratory comparison of phenotypic outcomes of induced variants or perturbation experiments.

    Given the adoption of the KOLF2.1S line within the UK-DRI and other laboratories as a reference line, side-by-side comparison of the genetic and phenotypic differences with the newly established KOLF2.1J is now warranted. In that sense, it was a pity that the authors did not directly include this line in their study. Additionally, and as also alluded to in the manuscript, we would like to urge for expansion of a single reference line to a panel of reference lines, including genetically female lines and those of other ethnicities. Equality, diversity, and inclusion have every place in this panel design as genetically diverse reference panels will be pivotal in truly appreciating how genetic diversity can influence cell states, functional phenotypes, and enable the broadest translations. Given the polygenic nature of most neurodegenerative diseases, we may only be able to capture the precise (genetic) circumstances under which risk genes for dementia may exert their effect if we study them in a wide range of genetic backgrounds and sift out the drivers of genetic risk from the modulators. 

    —Caleb Webber is a co-author of this comment.

    References:

    Volpato V, Webber C. Addressing variability in iPSC-derived models of human disease: guidelines to promote reproducibility. Dis Model Mech. 2020 Jan 17;13(1) PubMed.

    View all comments by Bart De Strooper

  2. This is a remarkable study by design, with extraordinary rigorous attention to detail and definition of genomic properties of cell lines to identify as neutral a cell line as is possible. The proposed reference cell line will be extremely useful to compare phenotypes and to generate -omic data for various differentiation, developmental, and gene-editing studies across laboratories. However, many studies on phenotypes related to late-onset disorders will likely require further extensive genetic and/or culture perturbations (e.g., stress, age acceleration, etc.), which, again, will introduce layers of variability. It should prove to be easier to interpret these against a well-characterized and neutral genetic “starting” background than for individual investigators to simply use cell lines that are at hand.

    It will be interesting to know whether this reference cell line is neutral against other late-onset neurodegenerative disorders, e.g., Parkinson’s Disease or ALS. It is challenging to try to study commonalities and differences between AD and other neurodegenerative disorders, and a reference cell line could be very helpful.

    For certain questions, e.g., to study the impact of aging on mid- or late-life disorders such as AD, or to study sex differences, this cell line may be insufficient. Several laboratories have published on iPSCs from sporadic late-life AD, with interesting findings, one noting that they have identified “person-specific processes” (e.g., Mertens et al., 2021; Lagomarsino et al., 2021). However, pooling genomic or other data across studies of sporadic AD iPSC lines may be challenging, and such studies might be strengthened by this reference cell line as a control in experiments where skin biopsies or iPSCs from a variety of donors are to be studied. This comment has some parallels with mouse models. For example, the C57BL mouse, which has been extensively sequenced, is used as a wild-type or background strain for many genetic and breeding manipulations. However, genetic diversity in mouse strains can help to understand aging-related phenomena, as with the Mighty Mouse Models of Memory and it is likely that studies of iPSCs derived from different human donors will provide knowledge to shed light on complexities of AD.

    References:

    Mertens J, Herdy JR, Traxler L, Schafer ST, Schlachetzki JC, Böhnke L, Reid DA, Lee H, Zangwill D, Fernandes DP, Agarwal RK, Lucciola R, Zhou-Yang L, Karbacher L, Edenhofer F, Stern S, Horvath S, Paquola AC, Glass CK, Yuan SH, Ku M, Szücs A, Goldstein LS, Galasko D, Gage FH. Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer's patients. Cell Stem Cell. 2021 Sep 2;28(9):1533-1548.e6. Epub 2021 Apr 27 PubMed.

    Lagomarsino VN, Pearse RV 2nd, Liu L, Hsieh YC, Fernandez MA, Vinton EA, Paull D, Felsky D, Tasaki S, Gaiteri C, Vardarajan B, Lee H, Muratore CR, Benoit CR, Chou V, Fancher SB, He A, Merchant JP, Duong DM, Martinez H, Zhou M, Bah F, Vicent MA, Stricker JM, Xu J, Dammer EB, Levey AI, Chibnik LB, Menon V, Seyfried NT, De Jager PL, Noggle S, Selkoe DJ, Bennett DA, Young-Pearse TL. Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors. Neuron. 2021 Nov 3;109(21):3402-3420.e9. Epub 2021 Sep 1 PubMed.

    View all comments by Douglas Galasko

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  1. KOLF2.1J: The Mother of All iPSC Lines?