15 Íîâîñòè êëåòî÷íûõ òåõíîëîãèé

15
Íîâîñòè êëåòî÷íûõ òåõíîëîãèé
ïîëó÷èâøèõ òðàíñïëàíòàòû îò äîíîðîâ ïðîòèâîïîëîæíîãî
ïîëà [8, 9, 11]. Áîëåå òîãî, Harris ïîêàçàë äèôôåðåíöèðîâêó ñòâîëîâûõ êëåòîê, ïîëó÷åííûõ èç êîñòíîãî ìîçãà, â
ë¸ãî÷íûé ýïèòåëèé áåç ñëèÿíèÿ in vivo [13].
Àâòîðû ñòàòüè ïðîòåñòèðîâàëè îáðàçöû òêàíåé íà ïîëèïëîèäèþ ñîïóòñòâóþùåé äåìîíñòðàöèåé Õ- è Y-õðîìîñîì. È õîòÿ êëåòîê ñ àíîìàëüíûì õðîìîñîìíûì íàáîðîì
îáíàðóæåíî íå áûëî, èññëåäîâàòåëè ñ÷èòàþò, ÷òî èç-çà ïðèðîäû ìàòåðèàëà âîçìîæíî áûëî ïðîâåñòè èñ÷åðïûâàþùèé
òåñò íà ïîëèïëîèäèþ.
Òàêèì îáðàçîì, â ðàáîòå ïîêàçàíî, ÷òî êëåòêè, ìèãðèðîâàâøèå â ë¸ãêèå èç âíåëåãî÷íîãî èñòî÷íèêà (â ÷àñòíîñòè êîñòíîãî ìîçãà), ñïîñîáíû ê ýíãðàôòèíãó è äèôôåðåíöèðîâêå
â êëåòêè àëüâåîëÿðíîãî ýïèòåëèÿ, à òàêæå â êëåòêè ìåçåíõèìàëüíîãî ïðîèñõîæäåíèÿ, âêëþ÷àÿ ìàêðîôàãè, ýíäîòåëèé è
ãëàäêèå ìèîöèòû. Ðàáîòà ïîäòâåðæäàåò, ÷òî òàêîé ìåõàíèçì
ðåïàðàòèâíîé ðåãåíåðàöèè âîçìîæåí â ë¸ãêèõ ÷åëîâåêà.
ËÈÒÅÐÀÒÓÐÀ:
1. Jiang Y., Jahagirdar B.N., Reinhardt R.L. et al. Pluripotency of mesenchymal
stem cells derived from adult marrow. Nature 2002; 418: 41-9.
2. Kotton D.N., Ma B.Y., Cardoso W.V. et al. Bone marrow-derived cells as
progenitors of lung alveolar epithelium. Development 2001; 128: 5181-8.
3. Okamoto R., Yajima T., Yamazaki M. et al. Damaged epithelia regenerated
by bone marrow-derived cells in the human gastrointestinal tract. Nat. Med. 2002;
8: 1011-7.
4. Ying Q.L., Nichols J., Evans E.P., Smith A.G. Changing potency by
spontaneous fusion. Nature 2002; 416: 545-8.
5. Krause D.S., Theise N.D., Collector M.I. et al. Multi-organ, multi-lineage
engraftment by a single bone marrow-derived stem cells. Cell 2001; 105:
369-77.
6. Theise N.D., Henegariu O., Grove J. et al. Radiation pneumonitis in mice: A
severe injury model for pneumocyte engraftment from bone marrow. Exp.
Haematol. 2002; 30: 1333-8.
7. Davies J.C., Potter M., Bush A. et al. Bone marrow stem cells do not
repopulate the healthy upper respiratory tract. Pediatr. Pulmonol. 2002; 34:
251-6.
Ïîäîáíûå ðàáîòû ìîãóò óêàçàòü íà íîâûå èíòåðåñíûå
âîçìîæíîñòè äëÿ ëå÷åíèÿ çàáîëåâàíèé ë¸ãêèõ. Êëåòêè, ïðèõîäÿùèå â ë¸ãêîå ïðè åãî ïîâðåæäåíèè, ïðåäñòàâëÿþò ñîáîé
ïîòåíöèàëüíî óïðàâëÿåìóþ ñèñòåìó, êîòîðàÿ ìîæåò èñïîëüçîâàòüñÿ äëÿ óñêîðåíèÿ âîññòàíîâëåíèÿ ýïèòåëèÿ ëåãêèõ.
 äîïîëíåíèå ê ýòîìó, âîçìîæíî, ðåïîïóëÿöèÿ ïîâðåæä¸ííûõ äûõàòåëüíûõ ïóòåé íîðìàëüíûìè êëåòêàìè ìîæåò áûòü
äîñòèãíóòà ïðè òðàíñïëàíòàöèè êîñòíîãî ìîçãà, êàê áûëî ïîêàçàíî äðóãèìè àâòîðàìè ïðè ëå÷åíèè ìóêîâèñöèäîçà [8].
Àâòîðû òàêæå ïðåäïîëàãàþò, ÷òî òðàíñïëàíòàöèÿ êîñòíîãî
ìîçãà ìîæåò áûòü èñïîëüçîâàíà â êà÷åñòâå äîïîëíèòåëüíîãî
òåðàïåâòè÷åñêîãî ñðåäñòâà ïðè ïðèìåíåíèè ãåííîé òåðàïèè.
Ýòà âîçìîæíîñòü áûëà èññëåäîâàíà íà ýêñïåðèìåíòàëüíîé
ìîäåëè è áûëî ïîêàçàíî, ÷òî ñòâîëîâûå êëåòêè êîñòíîãî ìîçãà
ìîãóò áûòü òðàíñôîðìèðîâàíû in vitro, à çàòåì, ïîñëå èìïëàíòàöèè, äèôôåðåíöèðîâàòüñÿ â äûõàòåëüíûé ýïèòåëèé
ïðàêòè÷åñêè áåç ïîòåðü ýêñïðåññèè òðàíñãåíîâ [14].
8. Suratt B.T., Cool C.D., Serls A.E. et al. Human pulmonary chimerism after
hematopoietic stem cell transplantation. Am. J. Respir. Crit. Care. Med. 2003;
168: 318-22.
9. Mattsson J., Jansson M., Wernerson A., Hassan M. Lung epithelial cells
and type II pneumocytes of donor origin after allogeneic hematopoietic stem cell
transplantation. Transplantation 2004; 78: 154-7.
10. Spees J.L., Olson S.D., Ylostalo J. et al. Differentiation, cell fusion and
nuclear fusion during ex vivo repair of epithelium by human adult stem cells from
bone marrow stroma. Proc. Natl. Acad. Sci. USA 2003; 100: 2397-402.
11. Kleeberger W., Versmold A., Rothamel T. et al. Increased chimerism of
bronchial and alveolar epithelium in human lung allografts undergoing chronic
injury. Am. J. Pathol. 2003; 162: 1487-9.
12. Vassilopoulos G., Wang P.R., Russell D.W. Transplanted bone marrow
regenerates liver by cell fusion. Nature 2003; 422: 901-4.
13. Harris R.G., Herzog E.L., Brusca E.M. et al. Lack of a fusion requirement
for development of bone marrow-derived epithelia. Science 2004; 305: 90-3.
14. Grove J.E., Lutzko C., Priller J. et al. Marrow-derived cells as vehicles for
delivery of gene therapy to pulmonary epithelium. Am. J. Respir. Cell Mol. Biol.
2002; 27: 645-51.
Ïîäãîòîâèëà À.Ñ. Ãðèãîðÿí
Ïî ìàòåðèàëàì Tissue Eng; 2005; 11: 1115
Ó÷àñòèå ñòâîëîâûõ êëåòîê âîëîñÿíîãî ôîëëèêóëà
â çàæèâëåíèè êîæíûõ ðàí
Èçâåñòíî, ÷òî êîæà è âîëîñû ìëåêîïèòàþùèõ õàðàêòåðèçóþòñÿ âûñîêîé ñêîðîñòüþ îáíîâëåíèÿ çà ñ÷¸ò ïðîëèôåðàöèè è äèôôåðåíöèðîâêè ïðîãåíèòîðíûõ êëåòîê. Ê ñòâîëîâûì
êëåòêàì (ÑÊ) âîëîñÿíîãî ôîëëèêóëà (ÂÔ), îòâåòñòâåííûì
ïðåæäå âñåãî çà ðîñò âîëîñà, îòíîñÿò 2 ïîïóëÿöèè, îäíà èç
êîòîðûõ ðàñïîëîæåíà â äåðìàëüíîì ñîñî÷êå íèæíåé ÷àñòè
ôîëëèêóëà, à äðóãàÿ - â áóãîðêå - bulge (ÁÂÔ), ëîêàëèçîâàííîì â âåðõíåé åãî ÷àñòè ïîä óñòüåì ñàëüíîé æåëåçû [1].
 íîðìå èõ ïðîëèôåðàöèÿ è äèôôåðåíöèðîâêà îáóñëàâëèâàþò ôîðìèðîâàíèå âñåõ òèïîâ êëåòîê ÂÔ, ñàëüíîé è ïîòîâîé æåëåç. Áûëî ïîêàçàíî, ÷òî â ðåïàðàöèè ïîâðåæäåíèÿ
êîæè ó÷àñòâóþò êàê áàçàëüíûå êëåòêè ýïèäåðìèñà, òàê è
êëåòêè äåðìàëüíîãî ñîñî÷êà [2]. Ó÷àñòèå êëåòîê áóãîðêà ÂÔ
â ðåãåíåðàöèè êîæè îñòà¸òñÿ íåèçó÷åííûì.
Ãðóïïîé Cotsarelis èç University of Pennsylvania áûëî óñòàíîâëåíî, ÷òî ñïåöèôè÷íûì ìàðê¸ðîì ñòâîëîâûõ êëåòîê
ÁÂÔ ÿâëÿåòñÿ âûñîêèé óðîâåíü ýêñïðåññèè áåëêà öèòîêåðàòèíà-15 [3]. Ðàíåå áûëî ïîêàçàíî, ÷òî ýòè êëåòêè êàê
ìèíèìóì áèïîòåíòíû è ìèãðèðóþò â ýïèäåðìèñ ôèçèîëîãè÷åñêè è â ïðîöåññå ðåãåíåðàöèè [5, 7]. Ïîçäíåå âûÿñíèëîñü,
÷òî êëåòêè ÁÂÔ îáëàäàþò ñâîéñòâàìè êëîíîãåííîñòè è ìóëüòèïîòåíòíû. Ïðè òðàíñïëàíòàöèè ïîñëå 140 óäâîåíèé â êóëüòóðå îíè äàâàëè íà÷àëî âñåì ëèíèÿì êëåòîê, ó÷àñòâóþùèì â
ôîðìèðîâàíèè âîëîñà. Ìíîãî÷èñëåííûå ôîëëèêóëû áûëè
ñôîðìèðîâàíû îò ïîòîìñòâà òîëüêî îäíîé ÑÊ [4]. Òàêèì îáðàçîì, ðàáîòû ðÿäà èññëåäîâàòåëüñêèõ ãðóïï äîêàçàëè, ÷òî
êëåòêè îáëàñòè ÁÂÔ ÿâëÿþòñÿ èñòèííûìè ÑÊ âçðîñëîãî
îðãàíèçìà ìëåêîïèòàþùèõ [1, 3-6].
Îòêðûòèå äîëãîæèâóùèõ ÑÊ â ýïèäåðìèñå è îáëàñòè ÁÂÔ,
ïðèâåëî ê ïîÿâëåíèþ ãèïîòåçû î òîì, ÷òî, âîçìîæíî, ýòè êëåòêè
ó÷àñòâóþò è â îáíîâëåíèè ýïèäåðìèñà â íîðìå, è ïðè çàæèâëåíèè êîæíûõ ðàí [1]. Äëÿ ïðîâåðêè ýòîé ãèïîòåçû ãðóïïà âî
ãëàâå ñ George Cotsarelis ïðîèçâåëà «ãåííóþ àáëÿöèþ» ýòèõ
êëåòîê, èñïîëüçóÿ èõ óíèêàëüíûé ìàðêåð - öèòîêåðàòèí-15.
 ðåçóëüòàòå ïîäîáíîé àáëÿöèè ðîñò âîëîñ ïðåêðàùàëñÿ ïî
ïðè÷èíå ïîëíîé äåãðàäàöèè ôîëëèêóëîâ, îäíàêî ýïèäåðìèñ
Êëåòî÷íàÿ òðàíñïëàíòîëîãèÿ è òêàíåâàÿ èíæåíåðèÿ ¹ 1 (3), 2006
16
Íîâîñòè êëåòî÷íûõ òåõíîëîãèé
îñòàâàëñÿ íåïîâðåæäåííûì. Èòîãîì ýêñïåðèìåíòà ñëóæèò
âûâîä î òîì, ÷òî ñòâîëîâûå êëåòêè ÂÔ è îáëàñòè áóãîðêà íå
èãðàþò çíà÷èòåëüíîé ðîëè â ôóíêöèîíèðîâàíèè íåïîñðåäñòâåííî êëåòîê êîæè. Ýòè äàííûå ïîäòâåðæäàþò, ÷òî ýïè-
Ñõåìà ñòðîåíèÿ âîëîñÿíîãî ôîëëèêóëà:
ÁÂÔ – áóãîðîê âîëîñÿíîãî ôîëëèêóëà
ËÈÒÅÐÀÒÓÐÀ:
1. Cotsarelis G., Sun T.T., Lavker R.M. Label-retaining cells resident in the
bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle,
and skin carcinogenesis. Cell 1990; 61: 1329-37.
2. Morasso M.I., Tomic-Canic M. Epidermal Stem Cells: the cradle of
epidermal determination, differentiation and wound healing. Biol. Cell 2005;
97: 173-83.
3. Liu Y., Lyle S., Yang Z., Cotsarelis G. Keratin 15 promoter targets putative
epithelial stem cells in the hair follicle bulge. J. Invest. Dermatol. 2003; 121: 963-8.
4. Claudinot S., Nicolas M., Oshima H. Et al. Long-term renewal of hair follicles
from clonogenic multipotent stem cells. Proc. Natl. Acad. Sci. USA 2005; 102(41):
14677-82.
òåëèé êîæè èìååò ñîáñòâåííûé íåçàâèñèìûé èñòî÷íèê
ñòâîëîâûõ ýëåìåíòî⠖ êëåòêè, ðàñïîëîæåííûå â áàçàëüíîì
ñëîå ýïèäåðìèñà, ó÷àñòâóþùèå â îáðàçîâàíèè òàê íàçûâàåìîé ýïèäåðìàëüíîé ïðîëèôåðàòèâíîé åäèíèöû (ÝÏÅ) [8].
Äàëüíåéøèå ýêñïåðèìåíòû ãðóïïû G. Cotsarelis ïîêàçàëè, ÷òî ïîñëå ïîâðåæäåíèÿ ýïèäåðìèñà êëåòêè èç îáëàñòè
ÁÂÔ (êîòîðûå ïðèíÿòî îòíîñèòü ê ñòâîëîâûì êëåòêàì âîëîñà)
ìèãðèðóþò â îáëàñòü äåôåêòà, ïðèîáðåòàÿ ýïèäåðìàëüíûé
ôåíîòèï. Îäíàêî, èññëåäîâàòåëè íå îáíàðóæèâàëè èõ â ðàíå
÷åðåç íåñêîëüêî íåäåëü. Ýòî ãîâîðèò î òîì, ÷òî îíè îòâå÷àþò çà ïåðâûé - ñðî÷íûé - îòâåò íà ïîâðåæäåíèå, ôîðìèðóÿ
áûñòðî äåëÿùóþñÿ è âïîñëåäñòâèè äèôôåðåíöèðóþùóþñÿ
êîðîòêî æèâóùóþ ïîïóëÿöèþ.
Òàêèì îáðàçîì, ñòâîëîâûå êëåòêè îáëàñòè ÁÂÔ îòâå÷àþò
çà áûñòðóþ ðåýïèòàëèçàöèþ ðàíû, äàâàÿ êîðîòêî æèâóùóþ,
ïåðåõîäíóþ, àêòèâíî äåëÿùóþñÿ è ìèãðèðóþùóþ ïîïóëÿöèþ.
Cèãíàëû, ïîñòóïàþùèå èç äåðìàëüíîãî ñîñî÷êà â áóãîðîê è
çàïóñêàþùèå ðåãåíåðàòèâíûå ïðîöåññû (Wnt/beta-catenin),
óæå âûÿâëåíû è èçó÷åíû [9]. Îäíàêî ìîëåêóëû, çàïóñêàþùèå
áûñòðûé îòâåò êëåòîê ÁÂÔ íà ïîâðåæäåíèå êîæíîãî ýïèòåëèÿ, äî ñèõ ïîð íå ÿñíû. Èäåíòèôèêàöèÿ òàêèõ ñèãíàëüíûõ
ìîëåêóë ïîçâîëèò ðàçðàáîòàòü ñïîñîáû áîðüáû ñ ãëóáîêèìè
ïîâðåæäåíèÿìè êîæè è äðóãèìè íàðóøåíèÿìè, íàïðèìåð, ñ
âîçðàñòíîé ýïèäåðìàëüíîé àòðîôèåé.
Öåííîñòü ðàáîòû ñîñòîèò â ôóíêöèîíàëüíîì ðàçäåëåíèè
äâóõ ãðóïï ñòâîëîâûõ êëåòîê - ýïèäåðìèñà è ÁÂÔ, à, çíà÷èò,
è â èõ áîëåå îñîçíàííîì è öåëåíàïðàâëåííîì èñïîëüçîâàíèè â êà÷åñòâå êëåòîê-ïåðåíîñ÷èêîâ òåðàïåâòè÷åñêèõ
ãåíîâ â çàáîëåâàíèÿõ âîëîñ è êîæè (îòäåëüíî).  ïðàêòè÷åñêîì îòíîøåíèè ðàáîòà ìîæåò âíåñòè è íåêîòîðûé âêëàä
â êîñìåòîëîãèþ - ïðè ëàçåðíîì óäàëåíèè íåæåëàòåëüíûõ
âîëîñ ïðîèñõîäèò àáëÿöèÿ òîëüêî êëåòîê ôîëëèêóëà, à öåëîñòíîñòü ýïèäåðìèñà â çíà÷èòåëüíîé ñòåïåíè íå èçìåíÿåòñÿ. Êðîìå òîãî, óíèêàëüíûå ñâîéñòâà 2 íåçàâèñèìûõ
ñòâîëîâûõ ïîïóëÿöèé âîëîñà ìîæíî áóäåò èñïîëüçîâàòü äëÿ
ëå÷åíèÿ àëîïåöèè è êîæíûõ ðàí.
5. Taylor G., Lehrer M.S., Jensen P.J. et al. Involvement of follicular stem cells
in forming not only the follicle but also the epidermis. Cell 2000; 102(4): 451-61.
6. Morris R.J., Liu Y., Marles L. et al. Capturing and profiling adult hair follicle
stem cells. Nat. Biotechnol. 2004; 22(4): 411-7
7. Tumbar T., Guasch G., Greco V. et al. Defining the epithelial stem cell niche
in skin. Science 2004; 303(5656): 359-63.
8. Ãðàôîâà Ã.ß. Öèòîàðõèòåêòîíèêà ýïèäåðìèñà è ýïèäåðìàëüíîïðîëèôåðàòèâíûå åäèíèöû (ÝÏÅ). Àðõèâ àíàò., ãèòîëîãèè è ýìáðèîë. 1982;
82(4): 73-85.
9. Van Mater D., Kolligs F.T., Dlugosz A.A., Fearon E.R. Transient activation of
beta-catenin signaling in cutaneous keratinocytes is sufficient to trigger the active
growth phase of the hair cycle in mice. Genes Dev. 2003; 17: 1219-24.
Ïîäãîòîâèëà Â.Ñ. Ìåëèõîâà
Ïî ìàòåðèàëàì Nat. Med. 2005; 11: 1351-4
Êëåòî÷íàÿ òðàíñïëàíòîëîãèÿ è òêàíåâàÿ èíæåíåðèÿ ¹ 1 (3), 2006