Scientists Whip Up Neurons from T Cells in the Blood

Japanese researchers have devised a new way to derive neurons from blood cells. Reporting in the February 18 Stem Cell Reports, scientists led by Wado Akamatsu and Hideyuki Okano, Keio University School of Medicine, Tokyo, detail how they turn circulating T cells into induced pluripotent stem cells. From these TiPSCs, they then made brain cells that can model aspects of neurodegenerative disease—in this case Parkinson’s. Blood cells are tricky to differentiate into neurons, but this protocol reportedly coaxes them to form neural tissue every bit as well as skin fibroblasts do, the investigators claim.

“I applaud the effort the authors have made,” wrote Shauna Yuan, University of California, San Diego, who was not involved in the study. “They have significantly improved the efficiency of neuronal differentiation from TiPSCs and the method seems robust.” 

Take Your Pick. T cell-derived IPSCs give rise to dopaminergic (left), GABAergic (middle), and glutamatergic (right) neurons. [Courtesy of Matsumoto et al., 2016.]

Collecting patient fibroblasts is a tad invasive, and the necessary skin biopsy can lead to bleeding, infection, and scarring. To make things easier on patients, some scientists have been working on ways to get induced pluripotent stem cells (iPSCs) from more readily accessible somatic cells.

Problems arise when trying to differentiate pluripotent cells, however. They retain an epigenetic “memory” of their previous cellular incarnation, which makes it hard to transform them into cells that normally would have come from a different lineage. For example, iPSCs made from fibroblasts readily form neurons, as both types of cell originate from the ectoderm layer in developing embryos. Blood cells, on the other hand, come from an inner layer—the mesoderm—and resist conversion into neurons.

To overcome this hurdle, co-first authors Takuya Matsumoto and Koki Fujimori combined the methodologies of two research groups. One lab previously figured out how to turn CD3-positive T cells into iPSCs (Seki et al., 2010). Another worked out how to turn iPSCs directly into neural stem cells by floating individual cells in a serum-free culture medium (Tropepe et al., 2001). This contrasts with the oft-used method of growing iPSCs into embryoid bodies—three-dimensional clumps of pluripotent stem cells that contain three germ layers—and then extracting neural stem cells from the ectoderm (Nori et al., 2011). 

In the current study, the researchers found that embryoid bodies from TiPSCs generated very few neural stem cells. However, in the direct, serum-free technique, TiPSCs differentiated into neural stem cells as readily as did iPSCs from fibroblasts. Using various reprogramming factors, the researchers could convert the neural precursors into dopaminergic, GABAergic, and glutamatergic neurons (see image above). The TiPSC-derived stem cells led to as many subtypes of neuron as fibroblast iPSCs did, and those neurons had virtually identical electrophysiological properties, the scientists claim.

To see whether neurons from TiPSCs could model facets of neurologic disease, Matsumoto and colleagues derived dopaminergic neurons from the T cells of a person carrying the PARK2 parkin mutation that causes early onset Parkinson’s disease. The neurons were susceptible to mitochondrial stress, slow in turning over damaged mitochondria, and flush with reactive oxygen species, similar to neurons created from patient fibroblasts. From this, the authors conclude that their method leads to patient-specific disease models that are comparable to those from skin cells. As blood can be frozen for long periods, this method may allow neurons to be derived from stored samples, the authors noted. They intend to model other neurological diseases with TiPSCs.

“As the field is seeking a less-invasive source of cells to generate patient-derived models, development of easy-to-use and efficient differentiation protocols for TiPSCs has obvious implications,” wrote Yuan. The method should now be replicated in other labs. However, Yuan noted one caveat. During T cell maturation, receptor genes recombine in a process known as T cell receptor (TCR) rearrangement. This permanent change to the DNA means the genome of mature T cells—and any iPSCs or neurons derived from them—differs from that of other somatic cells. And since TCR genes are expressed in the central nervous system, they may affect neurons (Komal et al., 2014). Though the authors reported that TCR rearrangement did not influence the efficiency of the iPSCs differentiation into neurons, Yuan wrote that more work should be performed to fully evaluate the kind of variability and limitations that could be brought on by this genomic change.—Gwyneth Dickey Zakaib

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References

Paper Citations

  1. Seki T, Yuasa S, Oda M, Egashira T, Yae K, Kusumoto D, Nakata H, Tohyama S, Hashimoto H, Kodaira M, Okada Y, Seimiya H, Fusaki N, Hasegawa M, Fukuda K. Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. Cell Stem Cell. 2010 Jul 2;7(1):11-4. PubMed.
  2. Tropepe V, Hitoshi S, Sirard C, Mak TW, Rossant J, van der Kooy D. Direct neural fate specification from embryonic stem cells: a primitive mammalian neural stem cell stage acquired through a default mechanism. Neuron. 2001 Apr;30(1):65-78. PubMed.
  3. Nori S, Okada Y, Yasuda A, Tsuji O, Takahashi Y, Kobayashi Y, Fujiyoshi K, Koike M, Uchiyama Y, Ikeda E, Toyama Y, Yamanaka S, Nakamura M, Okano H. Grafted human-induced pluripotent stem-cell-derived neurospheres promote motor functional recovery after spinal cord injury in mice. Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16825-30. Epub 2011 Sep 26 PubMed.
  4. Komal P, Gudavicius G, Nelson CJ, Nashmi R. T-cell receptor activation decreases excitability of cortical interneurons by inhibiting α7 nicotinic receptors. J Neurosci. 2014 Jan 1;34(1):22-35. PubMed.

Further Reading

Papers

  1. Mahairaki V, Ryu J, Peters A, Chang Q, Li T, Park TS, Burridge PW, Talbot CC Jr, Asnaghi L, Martin LJ, Zambidis ET, Koliatsos VE. Induced pluripotent stem cells from familial Alzheimer's disease patients differentiate into mature neurons with amyloidogenic properties. Stem Cells Dev. 2014 Dec 15;23(24):2996-3010. PubMed.
  2. Sproul AA. Being human: The role of pluripotent stem cells in regenerative medicine and humanizing Alzheimer's disease models. Mol Aspects Med. 2015 Jun-Oct;43-44:54-65. Epub 2015 Jun 19 PubMed.
  3. Golas MM, Sander B. Use of human stem cells in Huntington disease modeling and translational research. Exp Neurol. 2016 Apr;278:76-90. Epub 2016 Jan 27 PubMed.

Primary Papers

  1. Matsumoto T, Fujimori K, Andoh-Noda T, Ando T, Kuzumaki N, Toyoshima M, Tada H, Imaizumi K, Ishikawa M, Yamaguchi R, Isoda M, Zhou Z, Sato S, Kobayashi T, Ohtaka M, Nishimura K, Kurosawa H, Yoshikawa T, Takahashi T, Nakanishi M, Ohyama M, Hattori N, Akamatsu W, Okano H. Functional Neurons Generated from T Cell-Derived Induced Pluripotent Stem Cells for Neurological Disease Modeling. Stem Cell Reports. 2016 Mar 8;6(3):422-35. Epub 2016 Feb 18 PubMed.

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