Microchimerism: foreign cells that do us good

Cells from oth­er indi­vid­u­als can be found in all of us. These microchemera, which are exchanged dur­ing preg­nan­cy between a moth­er and her foe­tus, could play an essen­tial role in pro­tect­ing and repair­ing mater­nal tis­sues. Their prop­er­ties are attract­ing the inter­est of sci­en­tists, offer­ing new pos­si­bil­i­ties for inno­v­a­tive cell ther­a­pies¹.

Microchimerism is a fas­ci­nat­ing phe­nom­e­non, but one that is large­ly unknown to the gen­er­al pub­lic. It is pro­duced by a bidi­rec­tion­al trans­fer of cells between the foe­tus and the moth­er dur­ing preg­nan­cy. “This is non-self, which per­sists in our organ­ism in the form of a small quan­ti­ty of cells (…), genet­ic mate­r­i­al that is not ours”, explains Maria Sbeih, who devot­ed her doc­tor­al the­sis to this subject.

These for­eign cells can be passed on to us by our moth­ers via the pla­cen­ta (foetal microchimerism), or exchanged in utero with a twin (twin microchimerism). Some­times, how­ev­er, microchimerism can hold sur­pris­es. There are rare cas­es where indi­vid­u­als car­ry with­in them the genet­ic imprint of an “evanes­cent” twin (who dis­ap­peared at the embry­on­ic stage), or that of a “phan­tom aunt”, where the moth­er trans­mits to her child cells that her own evanes­cent twin had bequeathed to her decades earlier.

Nev­er­the­less, these very spe­cial cas­es should not obscure the gen­er­al rule of microchimerism, which is that moth­ers pass on mater­nal cells to their foe­tus­es and, con­verse­ly, each moth­er retains a liv­ing mem­o­ry of her preg­nan­cy. Foetal microchimerism is “detectable in the mother’s body for more than 30 years after child­birth”, explains Maria Sbeih. In order to sur­vive for such a long time, the microchimeric cells nes­tle in a microen­vi­ron­ment that is con­ducive to stem cells, such as the mother’s bone marrow.

Microchimerism also plays a key role in “the tol­er­ance of the foe­tus in the mother’s body”, explains Nathalie Lam­bert, direc­tor of the INSERM Autoim­mune Arthri­tis Unit in Mar­seille. In fact, when they cross the pla­cen­tal bar­ri­er, foetal cells go to the thy­mus, an organ that the researcher describes as “the school of tol­er­ance”. This mech­a­nism enables the mother’s body “to learn to accept the child she is car­ry­ing, with­out reject­ing it”, con­tin­ues the researcher. And, con­verse­ly, the foe­tus receives mater­nal cells that enable it to tol­er­ate the host (the mother).

While recent stud­ies describe the pos­i­tive and coop­er­a­tive func­tions of microchimeras for the body and tis­sue regen­er­a­tion, this has not always been the case. For a long time, these cells were con­sid­ered to be poten­tial agents of autoim­mune dis­eases. Nathalie Lam­bert, who was trained and edu­cat­ed in microchimerism by Lee Nel­son, a pio­neer in the field in the Unit­ed States, remem­bers tak­ing part in the first stud­ies link­ing microchimerism to autoim­mune dis­eases such as scle­ro­der­ma. “We assumed that these for­eign cells were attack­ing the mother’s immune cells, pro­vok­ing a graft-ver­sus-host reac­tion”, she recalls.

In the wake of this work, numer­ous stud­ies have sought to estab­lish a link between the pres­ence of microchimeras and autoim­mune dis­eases in women. But in sci­ence, a cor­re­la­tion does not nec­es­sar­i­ly imply cau­sa­tion. “Just because you find fire­men at the site of a fire doesn’t mean they start­ed it”, says the researcher, using the metaphor of jour­nal­ist Lise Barnéoud, who has writ­ten a book² on the sub­ject. In oth­er words, microchemera are not nec­es­sar­i­ly respon­si­ble for the inflam­ma­tion of the tis­sue they are direct­ed at. It also remained to be proven that, despite their rar­i­ty, these few cells could have quan­tifi­able immuno­log­i­cal func­tions. This is what the researcher is in the process of demon­strat­ing in mouse mod­els, where these micro­chem­i­cal cells are capa­ble of pro­duc­ing autoan­ti­bod­ies spe­cif­ic to rheuma­toid arthri­tis (an autoim­mune and degen­er­a­tive dis­ease that leads to chron­ic inflam­ma­tion of the joints).

“It took us many years to break out of this par­a­digm”, stress­es Nathalie Lam­bert, who believes that sci­en­tif­ic research is final­ly giv­ing microchimerism the atten­tion it deserves. This is the case of the “Cuta­neous Biol­o­gy” team (Insti­tut Cochin, INSERM-CNRS, Uni­ver­sité Paris Cité) to which Maria Sbeih was attached dur­ing her the­sis. Sci­en­tists have recent­ly demon­strat­ed³ that micro­chem­i­cals can have high­ly ben­e­fi­cial effects on the mother’s health, by help­ing to repair dam­aged tis­sues (includ­ing the skin). “We observed the activ­i­ty of microchimeric cells migrat­ing towards dam­aged areas, or skin wounds in the case of our team”, explains the biol­o­gist. The results were clear: microchimeras are involved in tis­sue repair, “either by secret­ing pro-heal­ing mol­e­cules or by adopt­ing the phe­no­type of the cells in the dam­aged tissue”.

Microchimerism forms a small ther­a­peu­tic genet­ic reser­voir with which we are all endowed. A series of med­i­cine cab­i­nets, made up of the genes of our chil­dren, our moth­ers, our grand­moth­ers and our old­er broth­ers and sis­ters, which have yet to reveal all their secrets. The medi­um-term ambi­tion of sci­en­tists is there­fore to find ways of exploit­ing these micro­chem­i­cal cells for ther­a­peu­tic purposes.

The pace of research has accel­er­at­ed in recent years. Nathalie Lam­bert and her team analysed the blood of 92 preg­nant women for the first time. They were able to deter­mine the “HLA typ­ing” of three gen­er­a­tions: the preg­nant woman, her moth­er and her child. Using cut­ting-edge tech­niques, they were able to iden­ti­fy the pres­ence of mater­nal and grand-mater­nal cells in the cord blood. The team is cur­rent­ly work­ing on the pub­li­ca­tion of an arti­cle show­ing a form of home­osta­sis (reg­u­la­tion, bal­ance) between the dif­fer­ent micro­chem­i­cal sources. “We dis­cov­ered that preg­nant women with a high mater­nal microchimerism (grand­moth­er) at the start of preg­nan­cy had less microchimerism in their foe­tus dur­ing this peri­od, sug­gest­ing pos­si­ble com­pe­ti­tion between microchimeras to bal­ance the over­all quan­ti­ty”, explains the researcher from Marseilles.

From a cere­bral point of view, it has also been shown that foetal microchimerism can play a role in the repair of cere­bral lesions. Maria Sbeih reports “hav­ing observed⁴ real dif­fer­ences between mul­ti­parous (hav­ing had at least one preg­nan­cy) and nul­li­parous (the oppo­site) ani­mal mod­els in terms of their abil­i­ty to repair neu­ronal lesions”. Oth­er stud­ies tend to show⁵ that post-stroke recov­ery is more effec­tive in mul­ti­parous ani­mal mod­els, “with bet­ter revas­cu­lar­i­sa­tion of the dam­aged area”. While much remains to be dis­cov­ered about the pre­cise prop­er­ties of microchimeric cells, the sim­ple fact of hav­ing this ther­a­peu­tic poten­tial with­in us could make it pos­si­ble “to bypass many of the tech­ni­cal com­plex­i­ties asso­ci­at­ed with cur­rent cell ther­a­pies”, Maria Sbeih is delight­ed to report, “such as hav­ing to har­vest stem cells, puri­fy them, ampli­fy them, reim­plant them, etc.”.

Dis­creet as they may be, microchimeras could soon be mak­ing a big splash in the world of regen­er­a­tive medicine.

Samuel Belaud