Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Apr 11;13(8):666.
doi: 10.3390/cells13080666.

Chromosome Transplantation: Opportunities and Limitations

Angela La Grua  1   2 , Ilaria Rao  2   3 , Lucia Susani  2   4 , Franco Lucchini  5 , Elena Raimondi  6 , Paolo Vezzoni  2   4 , Marianna Paulis  2   4
Affiliations
Review

Chromosome Transplantation: Opportunities and Limitations

Angela La Grua et al. Cells. .

Abstract

There are thousands of rare genetic diseases that could be treated with classical gene therapy strategies such as the addition of the defective gene via viral or non-viral delivery or by direct gene editing. However, several genetic defects are too complex for these approaches. These "genomic mutations" include aneuploidies, intra and inter chromosomal rearrangements, large deletions, or inversion and copy number variations. Chromosome transplantation (CT) refers to the precise substitution of an endogenous chromosome with an exogenous one. By the addition of an exogenous chromosome and the concomitant elimination of the endogenous one, every genetic defect, irrespective of its nature, could be resolved. In the current review, we analyze the state of the art of this technique and discuss its possible application to human pathology. CT might not be limited to the treatment of human diseases. By working on sex chromosomes, we showed that female cells can be obtained from male cells, since chromosome-transplanted cells can lose either sex chromosome, giving rise to 46,XY or 46,XX diploid cells, a modification that could be exploited to obtain female gametes from male cells. Moreover, CT could be used in veterinary biology, since entire chromosomes containing an advantageous locus could be transferred to animals of zootechnical interest without altering their specific genetic background and the need for long and complex interbreeding. CT could also be useful to rescue extinct species if only male cells were available. Finally, the generation of "synthetic" cells could be achieved by repeated CT into a recipient cell. CT is an additional tool for genetic modification of mammalian cells.

Keywords: Duchenne muscular dystrophy; X chromosome; chromosome transplantation; genomic disease; iPSC.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic overview of the CT approach: the diagram illustrates the three main steps. 1. Generation of recipient male (XY) iPSCs containing a defective X chromosome (depicted in red), and a donor cell line (LA9 or CHO) capable of forming microcells, containing a normal X chromosome (depicted in green). 2. Fusion between microcells and recipient X-defective cells, followed by the selection of XXY cells. 3. Elimination of the extra sex chromosome (either Y or defective X), resulting in the generation of a normal CT euploid XX or XY iPSC line.
Figure 2
Figure 2
Schematic overview of the retro-MMCT approach: the diagram illustrates the main steps. 1. A donor cell line containing a normal human X chromosome (CHO/HSAX) is infected with the EnvΔR lentivirus. 2–3. Colcemid treatment induces micronucleation and after centrifugation microcells from the donor cells are obtained; 4–5. Microcells are co-cultured with the recipient iPSCs to induce EnvΔR-mediated cell–microcell fusion. 6. The resulting fused cells are selected to identify those in which the normal HSAX has been acquired.
Figure 3
Figure 3
Representative images illustrate the occurrence of spontaneous in vitro loss of an extra sex chromosome. We isolated cells that spontaneously lost either the additional X or the Y chromosome in both mouse (A) and human (B) cells. (A) Representative karyotype (left) and metaphase spread (middle) following FISH with probes for the mouse X chromosome (green) and Y chromosome (red) are presented. On the right are two representative karyotypes of cells obtained after a few passages in culture from the original 41,XXY, showing the presence of cells that have spontaneously lost the extra sex chromosome (40,XY or 40,XX). (B) Representative karyotype (left) and metaphase spread (middle) following FISH with a probe for the human X chromosome (green) are shown. The human Y chromosome (#) is identified by banding. On the right are two representative karyotypes of cells obtained after a few passages in culture from the original 47,XXY, indicating the presence of cells that have spontaneously lost the extra sex chromosome (46,XY or 46,XX).
Figure 4
Figure 4
Possible applications of CT.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Ferrari S., Valeri E., Conti A., Scala S., Aprile A., Di Micco R., Kajaste-Rudnitski A., Montini E., Ferrari G., Aiuti A., et al. Genetic engineering meets hematopoietic stem cell biology for next-generation gene therapy. Cell Stem Cell. 2024;30:549–570. doi: 10.1016/j.stem.2023.04.014. - DOI - PubMed
    1. Fischer A. Gene therapy for inborn errors of immunity: Past, present and future. Nat. Rev. Immunol. 2023;23:397–408. doi: 10.1038/s41577-022-00800-6. - DOI - PubMed
    1. Lupski J.R. Genomic disorders: Structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet. 1998;14:417–422. doi: 10.1016/S0168-9525(98)01555-8. - DOI - PubMed
    1. Ege T., Ringertz N.R. Preparation of microcells by enucleation of micronucleate cells. Exp. Cell Res. 1974;87:378–382. doi: 10.1016/0014-4827(74)90494-7. - DOI - PubMed
    1. Fournier R.E., Ruddle F.H. Microcell-mediated transfer of murine chromosomes into mouse, Chinese hamster, and human somatic cells. Proc. Natl. Acad. Sci. USA. 1977;74:319–323. doi: 10.1073/pnas.74.1.319. - DOI - PMC - PubMed

Publication types

LinkOut - more resources