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